Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity

ABSTRACT

Template-fixed β-hairpin peptidomimetics of the general formulae 
                         
wherein Z is a chain of 11 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid) are Gly, or Pro, or Pro(4NHCOPhe), or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have the property to inhibit proteases, in particular serine proteases, especially Cathepsin G or Elastase or Tryptase. These β-hairpin peptidomimetics can be manufactured by processes which are based on a mixed solid- and solution phase synthetic strategy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent application Ser. No. 15/170,233, filed on Jun. 1, 2016, which in turn is a continuation application of U.S. patent application Ser. No. 14/100,878, filed on Dec. 9, 2013, which in turn is a divisional application of U.S. patent application Ser. No. 11/816,589, filed on Oct. 5, 2007, now U.S. Pat. No. 8,658,604, issued Feb. 25, 2014, which application is the National Stage of International Application No. PCT/EP2005/001622, filed Feb. 17, 2005, the entire contents of each of which is incorporated by reference herein.

FIELD OF THE INVENTION

The present invention provides template-fixed β-hairpin peptidomimetics incorporating a template-fixed chain of 11 α-amino acid residues which, depending on their position in the chain, are Gly, or Pro, or Pro(4NHCOPhe), or are of certain types, as defined hereinbelow. These template-fixed β-hairpin peptidomimetics are useful as inhibitors of protease enzymes. They are especially valuable as inhibitors of various serine proteases such as human cathepsin G, elastase, or tryptase. In addition the present invention provides an efficient process by which these compounds can, if desired, be made in library-format.

The β-hairpin peptidomimetics of the invention show improved efficacy, oral bioavailability, improved half-life and most importantly a high selectivity ratio among different serine proteases which depends on the proper choice of certain types of α-amino acid residues and their position in said chain. In addition these β-hairpin peptidomimetics show a low hemolysis on red blood cells and low cytotoxicity.

BACKGROUND OF THE INVENTION

Inhibitors of proteases are emerging with promising therapeutic uses in the treatment of diseases such as cancers (R. P. Beckett, A. Davidson, A. H. Drummond, M. Whittaker, Drug Disc. Today 1996, 1, 16-26; L. L. Johnson, R. Dyer, D. J. Hupe, Curr. Opin. Chem. Biol. 1998, 2, 466-71; D. Leung, G. Abbenante, and D. P. Fairlie, J. Med. Chem. 2000, 43, 305-341, T. Rockway, Expert Opin. Ther. Patents 2003, 13, 773-786), parasitic, fungal, and viral infections [e.g. schistosomiasis (M. M. Becker, S. A. Harrop, J. P. Dalton, B. H. Kalinna, D. P. McManus, D. P. Brindley, J. Biol. Chem. 1995, 270, 24496-501); C. albicans (C. Abad-Zapetero, R. Goldman, S. W. Muchmore, C. Hutchins, K. Stewart, J. Navaza, C. D. Payne, T. L. Ray, Protein Sci. 1996, 5, 640-52), HIV (A. Wlodawer, J. W. Erickson, Annu. Rev. Biochem. 1993, 62, 543-85; P. L. Darke, J. R. Huff, Adv. Phannacol. 1994, 5, 399-454), hepatitis (J. L. Kim, K. A. Morgenstern, C. Lin, T. Fox, M. D. Dwyer, J. A. Landro, S. P. Chambers, W. Markland, C. A. Lepre, E. T. O'Malley, S. L. Harbeson, C. M. Rice, M. A. Murcko, P. R. Caron, J. A. Thomson, Cell, 1996, 87, 343-55; R. A. Love, H. E. Parge, J. A. Wickersham, Z. Hostomsky, N. Habuka, E. W. Moomaw, T. Adachi, Z. Hostomska, Cell, 1996, 87, 331-342), herpes (W. Gibson, M. R. Hall, Drug. Des. Discov. 1997, 15, 39-47)], and inflammatory, immunological, respiratory (P. R. Bernstein, P. D. Edwards, J. C. Williams, Prog. Med. Chem. 1994, 31, 59-120; T. E. Hugh, Trends Biotechnol. 1996, 14, 409-12,), cardiovascular (M. T. Stubbs, W. A. Bode, Thromb. Res. 1993, 69, 1-58; H. Fukami et al, Current Pharmaceutical Design 1998, 4, 439-453), and neurodegenerative defects including Alzheimer's disease (R. Vassar, B. D. Bennett, S. Babu-Kahn, S. Kahn, E. A. Mendiaz, Science, 1999, 286, 735-41), angiogenesis (Kaatinen M et al, Atherosklerosis 1996, 123 1-2, 123-131) and multiple sclerosis (Ibrahim M Z et al, J. Neuroimmunol 1996, 70, 131-138.

As most proteases bind their substrates in extended or β-strand conformations, good inhibitors must thus be able to mimic such a conformation. β-Hairpin mimetics are thus ideally suited to lock peptide sequences in an extended conformation.

Among proteases, serine proteases constitute important therapeutic targets. Serine proteases are classified by their substrate specificity, particularly by the type of residue found at P1, as either trypsin-like (positively charged residues Lys/Arg preferred at P1), elastase-like (small hydrophobic residues Ala/Val at P1), or chymotrypsin-like (large hydrophobic residues Phe/Tyr/Leu at P1). Serine proteases for which protease-inhibitor X-ray crystal data is available on the PDB data base (PDB: www.rcsb.org/pdb) include trypsin, α-chymotrypsin, γ-chymotrypsin, human neutrophil elastase, thrombin, subtilisin, human cytomegalovirus, proteinase A, achromobacter, human cathepsin G, glutamic acid-specific protease, carbopeptidase D, blood coagulation factorVIIa, porcine factor 1XA, mesentericopeptidase, HCV protease, and thermitase. Other serine proteases which are of therapeutic interest include tryptase, complement convertase, hepatitis C-NS3 protease. Inhibitors of thrombin (e.g. J. L. Metha, L. Y. Chen, W. W. Nichols, C. Mattsson, D. Gustaffson, T. G. P. Saldeen, J. Cardiovasc. Phannacol. 1998, 31, 345-51; C. Lila, P. Gloanec, L. Cadet, Y. Herve, J. Fournier, F. Leborgne, T. J. Verbeuren, G. DeNanteuil, Synth. Comm. 1998, 28, 4419-29) and factor Xa (e.g. J. P. Vacca, Annu. Rep. Med. Chem. 1998, 33, 81-90) are in clinical evaluation as anti-thrombotics, inhibitors of elastase (J. R. Williams, R. C. Falcone, C. Knee, R. L. Stein, A. M. Strimpler, B. Reaves, R. E. Giles, R. D. Krell, Am. Rev. Respir. Dis. 1991, 144, 875-83) are in clinical trials for emphysema and other pulmonary diseases whereas tryptase inhibitors are currently in phase II clinical trials for asthma (C. Seife, Science 1997, 277, 1602-3), urokinase inhibitors for breast cancer, and chymase inhibitors for heart related diseases. Finally, cathepsin G and elastase are intimately involved in the modulation of activities of cytokines and their receptors. Particularly at sites of inflammation, high concentration of cathepsin G, elastase and proteinase 3 are released from infiltrating polymorphonuclear cells in close temporal correlation to elevated levels of inflammatory cytokines, strongly indicating that these proteases are involved in the control of cytokine bioactivity and availability (U. Bank, S. Ansorge, J. Leukoc. Biol. 2001, 69, 177-90). Thus inhibitors of elastase and cathepsin G constitute valuable targets for novel drug candidates particularly for chronic obstructive pulmonary disease (Ohbayashi H, Epert Opin. Investig. Drugs 2002, 11, 965-980).

Of the many occurring proteinaceous serine protease inhibitors, one is a 14 amino acid cyclic peptide from sunflower seeds, termed sunflower trypsin inhibitor (SFTI-1) (S. Luckett, R. Santiago Garcia, J. J. Barker, A. V. Konarev, P. R. Shewry, A. R. Clarke, R. L. Brady, J. Mol. Biol. 1999, 290, 525-533; Y.-Q. Long, S.-L. Lee, C.-Y. Lin, I. J. Enyedy, S. Wang, P. Li, R. B. Dickson, P. P. Roller, Biorg. & Med. Chem. Lett. 2001, 11, 2515-2519), which shows both sequence and conformational similarity with the trypsin-reactive loop of the Bowman-Birk family of serine protease inhibitors. The inhibitor adopts a β-hairpin conformation when bound to the active site of bovine β-trypsin. SFTI-1 inhibited β-trypsin (K_(i)<0.1 nM), cathepsin G (K_(i)˜0.15 nM), elastase (K_(i)˜105 μM), chymotrypsin (K_(i)˜7.4 μM) and thrombin (K_(i)˜136 mM).

BRIEF SUMMARY OF THE INVENTION

We illustrate here an approach to inhibitor design which involves transplanting the β-hairpin loop from the naturally occurring peptide onto a hairpin-inducing template. Based on the well defined 3D-structure of the β-hairpin mimetics, libraries of compounds can be designed which ultimately can lead to novel inhibitors showing different specificity profiles towards several classes of proteases.

Template-bound hairpin mimetic peptides have been described in the literature (D, Obrecht, M. Altorfer, J. A. Robinson, Adv. Med. Chem. 1999, 4, 1-68; J. A. Robinson, Syn. Lett. 2000, 4, 429-441), and serine proteinase-inhibiting template-fixed peptidomimetics and methods for their synthesis have been described in International Patent Application WO2003/054000 A1 and in Descours A, Moehle K., Renard A, Robinson J. ChemBioChem 2002, 3, 318-323 but the previously disclosed molecules do not exhibit high selectivity and particularly high potency. However, the ability to generate β-hairpin peptidomimetics using combinatorial and parallel synthesis methods has now been established (L. Jiang, K. Moehle, B. Dhanapal, D. Obrecht, J. A. Robinson, Helv. Chim. Acta. 2000, 83, 3097-3112).

These methods allow the synthesis and screening of large hairpin mimetic libraries, which in turn considerably facilitates structure-activity studies, and hence the discovery of new molecules with highly potent and selective serine protease inhibitory activity, oral bioavailability, low hemolytic activity to human red blood cells and low cytotoxicity.

DETAILED DESCRIPTION OF THE INVENTION

The β-hairpin peptidomimetics of the present invention are compounds of the general formula

wherein

is a group of one of the formulae

wherein

is Gly or the residue of an L-α-amino acid with B being a residue of formula —NR²⁰CH(R⁷¹)— or the enantiomer of one of the groups A1 to A69 as defined hereinafter;

is a group of one of the formulae

-   R¹ is H; lower alkyl; or aryl-lower alkyl; -   R² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)N³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶)₂; —(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R⁶ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;     —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;     —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;     —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s) C₆H₄R⁸; -   R⁸ is H; Cl; F; CF₃; NO₂; lower alkyl; lower alkenyl; aryl;     aryl-lower alkyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵,     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶, —(CH₂)_(o)(CHR⁶¹)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴; -   R⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R¹⁰ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R¹¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;     —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;     —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;     —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸; -   R¹² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(r)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸; -   R¹³ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(q)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸; -   R¹⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;     —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;     —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;     —(CH₂)_(q)(CHR⁶¹)_(s)SOR⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s) C₆H₄R⁸; -   R¹⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R¹⁶ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R¹⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(r)NR³³R³⁴;     —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(q)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸; -   R¹⁸ is alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)₅NR³³R³⁴;     —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R¹⁹ is lower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     (CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or -   R¹⁸ and R¹⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;     —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; -   R²⁰ is H; alkyl; alkenyl; or aryl-lower alkyl; -   R²¹ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R²² is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R²³ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(r)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(r)PO(OR⁶)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R²⁴ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R²⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R²⁶ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²,     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or -   R²⁵ and R²⁶ taken together can form: —(CH₂)₂₋₆—;     —(CH₂)_(r)O(CH₂)_(r)—; —(CH₂)_(r)S(CH₂)_(r)—; or     —(CH₂)_(r)NR⁵⁷(CH₂)_(r)—; -   R²⁷ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R²⁸ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)—OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s) SR⁵⁶, —(CH₂)_(o)(CHR⁶¹)_(s) NR³³ _(R) ³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s) COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s) CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s) PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸; -   R²⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R³⁰ is H; alkyl; alkenyl; or aryl-lower alkyl; -   R³¹ is H; alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;     —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;     —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;     —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R³² is H; lower alkyl; or aryl-lower alkyl; -   R³³ is H; alkyl, alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)—CONR⁵⁸R⁵⁹, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;     —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R³⁴ is H; lower alkyl; aryl, or aryl-lower alkyl; -   R³³ and R³⁴ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;     —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; -   R³⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;     —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;     —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s) C₆H₄R⁸; -   R³⁶ is H, alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(p)(CHR⁶¹)_(s)N³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;     —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;     —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;     —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R³⁷ is H; F; Br; Cl; NO₂; CF₃; lower alkyl;     —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R³⁸ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;     —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R³⁹ is H; alkyl; alkenyl; or aryl-lower alkyl; -   R⁴⁰ is H; alkyl; alkenyl; or aryl-lower alkyl; -   R⁴¹ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;     —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸; -   R⁴² is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;     —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or     —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸; -   R⁴³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;     —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;     —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R⁴⁴ is alkyl; alkenyl; —(CH₂)_(r)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(r)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(r)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(r)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(r)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(r)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸; -   R⁴⁵ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(s)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(s)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(s)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(s)(CHR⁶¹)_(s)C₆H₄R⁸; -   R⁴⁶ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(p)C₆H₄R⁸; -   R⁴⁷ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; -   R⁴⁸ is H; lower alkyl; lower alkenyl; or aryl-lower alkyl; -   R⁴⁹ is H; alkyl; alkenyl; —(CHR⁶¹)_(s)COOR⁵⁷;     (CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CHR⁶¹)_(s)SOR⁶²; or     —(CHR⁶¹)_(s)C₆H₄R⁸; -   R⁵⁰ is H; lower alkyl; or aryl-lower alkyl; -   R⁵¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸; -   R⁵² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or     —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸; -   R⁵³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or     —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸; -   R⁵⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;     —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³e;     —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷;     —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; -   R⁵⁵ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;     —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;     —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; or     —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; -   R⁵⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;     —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;     —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴; or —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; -   R⁵⁷ is H; lower alkyl; lower alkenyl; aryl lower alkyl; or     heteroaryl lower alkyl; -   R⁵⁸ is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower     alkyl; or heteroaryl-lower alkyl; -   R⁵⁹ is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower     alkyl; or heteroaryl-lower alkyl; or -   R⁵⁸ and R⁵⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;     —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; -   R⁶⁰ is H; lower alkyl; lower alkenyl; aryl; or aryl-lower alkyl; -   R⁶¹ is alkyl; alkenyl; aryl; heteroaryl; aryl-lower alkyl;     heteroaryl-lower alkyl; —(CH₂)_(m)OR⁵⁵; —(CH₂)_(m)NR³³R³⁴;     —(CH₂)_(m)OCONR⁷⁸R⁸²; —(CH₂)_(o)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)COOR³⁷;     —(CH₂)_(o)NR⁵⁸R⁵⁹; or —(CH₂)_(o)PO(COR⁶⁰)₂; -   R⁶² is lower alkyl; lower alkenyl; aryl, heteroaryl; or aryl-lower     alkyl; -   R⁶³ is H; lower alkyl; lower alkenyl; aryl, heteroaryl; aryl-lower     alkyl; heteroaryl-lower alkyl; —COR⁶⁴; —COOR⁵⁷; —CONR⁵⁸R⁵⁹; —SO₂R⁶²;     or —PO(OR⁶⁰)₂; -   R³⁴ and R⁶³ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;     —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; -   R⁶⁴ is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower     alkyl; heteroaryl-lower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁶⁵;     —(CH₂)_(p)(CHR⁶¹)_(s)SR⁶⁶; or —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴R⁶³;     —(CH₂)_(p)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; -   R⁶⁵ is H; lower alkyl; lower alkenyl; aryl, aryl-lower alkyl;     heteroaryl-lower alkyl; —COR⁵⁷; —COOR⁵⁷; or —CONR⁵⁸R⁵⁹; -   R⁶⁶ is H; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl;     heteroaryl-lower alkyl; or —CONR⁵⁸R⁵⁹; -   m is 2-4; o is 0-4; p is 1-4; q is 0-2; r is 1 or 2; s is 0 or 1;

Z is a chain of 11 α-amino acid residues, the positions of said amino acid residues in said chain being counted starting from the N-terminal amino acid, whereby these amino acid residues are, depending on their position in the chains, Gly, Pro, Pro(4NHCOPhe) or of formula -A-CO—, or of formula —B—CO—, or of one of the types

-   C: —NR²⁰CH(R⁷²)CO—; -   D: —NR²⁰CH(R⁷³)CO—; -   E: —NR²⁰CH(R⁷⁴)CO—; -   F: —NR²⁰CH(R⁸⁴)CO—; and -   H: —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;     —NR²⁰—CH(CO—)—(CH₂)_(p)S(CH₂)_(p)—CH(CO—)—NR²⁰—;     —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; and     —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—; -   R⁷¹ is lower alkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁷⁵;     —(CH₂)_(p)(CHR⁶¹)_(s)SR⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;     —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;     —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁷⁵; —(CH₂)_(p)CONR⁵⁸R⁵⁹;     —(CH₂)_(p)PO(OR⁶²)₂; —(CH₂)_(p)SO₂R⁶²; or     —(CH₂)_(o)—C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶; -   R⁷² is H, lower alkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁸⁵; or     —(CH₂)_(p)(CHR⁶¹)_(s)SR⁸⁵; -   R⁷³ is —(CR⁸⁶R⁸⁷)_(o)R⁷⁷; —(CH₂)_(r)O(CH₂)_(o)R⁷⁷;     —(CH₂)_(r)S(CH₂)_(o)R⁷⁷; or —(CH₂)_(r)NR²⁰(CH₂)_(o)R⁷⁷; -   R⁷⁴ is —(CH₂)_(p)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁷⁷R⁸⁰;     —(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;     —(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;     —(CH₂)_(p)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CH₂)_(p)C₆H₄NR⁷⁸R⁷⁹;     —(CH₂)_(p)C₆H₄NR⁷⁷R⁸⁰; —(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;     —(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;     —(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NOR⁷⁹; —(CH₂)_(p)C₆H₄N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;     —(CH₂)_(r)O(CH₂)_(m)NR⁷⁸R⁷⁹; —(CH₂)_(r)O(CH₂)_(m)NR⁷⁷R⁸⁰;     —(CH₂)_(r)O(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;     —(CH₂)_(r)O(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;     —(CH₂)_(r)O(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;     —(CH₂)_(i)O(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;     —(CH₂)_(r)O(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;     —(CH₂)_(r)O(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;     —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;     —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;     —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;     —(CH₂)_(r)O(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;     —(CH₂)_(r)S(CH₂)NR⁷⁸R⁷⁹; —(CH₂)_(r)S(CH₂)_(m)NR⁷⁷R⁸⁰;     —(CH₂)_(r)S(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;     —(CH₂)_(r)S(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;     —(CH₂)_(r)S(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;     —(CH₂)_(r)S(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;     —(CH₂)_(r)S(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;     —(CH₂)_(r)S(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;     —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;     —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;     —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;     —(CH₂)_(r)S(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰COR⁶⁴;     —(CH₂)_(p)NR⁸⁰COR⁷⁷; —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹;     —(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹; or     —(CH₂)_(p)NR²⁰CO—[(CH₂)_(u)—X]_(t)—CH₃ where X is —O—; —NR²⁰—, or     —S—; u is 1-3, and t is 1-6; -   R⁷⁵ is lower alkyl; lower alkenyl; or aryl-lower alkyl; -   R³³ and R⁷⁵ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;     —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; -   R⁷⁵ and R⁸² taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;     —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; -   R⁷⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;     —(CH₂)_(m)OR⁷²; —(CH₂)_(o)SR⁷²; —(CH₂)_(o)NR³³R³⁴;     —(CH₂)_(o)OCONR³³R⁷⁵; —(CH₂)_(o)NR²⁰CONR³³R⁸²; —(CH₂)_(o)COOR⁷⁵;     —(CH₂)_(o)CONR⁵⁸R⁵⁹; —(CH₂)_(o)PO(OR⁶⁰)₂; —(CH₂)_(p)SO₂R⁶²; or     —(CH₂)_(o)COR⁶⁴; -   R⁷⁷ is —C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶; or a heteroaryl group of one of the     formulae

-   R⁷⁸ is H; lower alkyl; aryl; or aryl-lower alkyl; -   R⁷⁸ and R⁸² taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;     —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; -   R⁷⁹ is H; lower alkyl; aryl; or aryl-lower alkyl; or -   R⁷⁸ and R⁷⁹, taken together, can be —(CH₂)₂₋₇—: —(CH₂)₂O(CH₂)₂—; or     —(CH₂)₂NR⁵⁷(CH₂)₂—; -   R⁸⁰ is H; or lower alkyl; -   R⁸¹ is H; lower alkyl; or aryl-lower alkyl; -   R⁸² is H; lower alkyl; aryl; heteroaryl; or aryl-lower alkyl; -   R³³ and R⁸² taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;     —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; -   R⁸³ is H; lower alkyl; aryl; or —NR⁷⁸R⁷⁹; -   R⁸⁴ is —(CH₂)_(m)(CHR⁶¹)_(s)OH; —(CR⁸⁶R⁸⁷)pOR⁸⁰; —(CR⁸⁶R⁸⁷)pCOOR⁸⁰;     —(CH₂)_(m)(CHR⁶¹)_(s)SH; —(CR⁸⁶R⁸⁷)pSR⁸⁰; —(CH₂)_(p)CONR⁷⁸R⁷⁹;     —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄CONR⁷⁸R⁷⁹;     —(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹; —(CR⁸⁶R⁸⁷)_(o)PO(OR⁶⁰)₂;     —(CR⁸⁶R⁸⁷)_(p)SO₂R⁶⁰; —(CR⁸⁶R⁸⁷)_(p)SOR⁶⁰; —(CH₂)_(m)(CHR⁶¹)_(s)     OPO(OR⁶⁰)₂; or —(CH₂)_(m)(CHR⁶¹)_(s) OSO₂R⁶⁰; -   R⁸⁵ is lower alkyl; or lower alkenyl; -   R⁸⁶ is H; lower alkyl, where H is maybe substituted by halogen; or     halogen; -   R⁸⁷ is H; lower alkyl, where H is maybe substituted by halogen; or     halogen; with the proviso that in said chain of 11 α-amino acid     residues Z     -   if n is 11, the amino acid residues in positions 1 to 11 are:         -   P1: of type C or of type D or of type E or of type F;         -   P2: of type C or of Type D or of type E, or of type F;         -   P3: or of type C, of type F, or the residue is Gly;         -   P4: of type C, or of type D, or of type F, or of type E, or             the residue is Gly or Pro;         -   P5: of type E, or of type C, or of type F, or the residue is             Gly or Pro;         -   P6: of type D, or of type F, or of type E or of type C, or             the residue is Gly or Pro;         -   P7: of type C, or of type E, or of type F, or of formula             -A-CO—, or the residue is Gly or Pro;         -   P8: of type D, or of type C, or of type F, or of formula             -A-CO, or the residue is Gly or Pro or Pro(4NHCOPhe);         -   P9: of type C, or of type D, or of type E, or of type F;         -   P10: of type D, or of type C, or of type F, or of type E;             and         -   P11: of type C, or of type D, or of type E, or of type F; or         -   P2 and P10, taken together, can form a group of type H; and     -   with the further proviso that if the template is ^(D)Pro^(L)Pro,         the amino acid residues in positions P1 to P11 are other than         -   P1: Arg         -   P2: Cys, linked with Cys in position P10 by a disulfide             bridge         -   P3: Thr         -   P4: Lys         -   P5: Ser         -   P6: Ile         -   P7: Pro         -   P8: Pro         -   P9: Ile         -   P10: Cys, linked with Cys in position P2 by a disulfide             bridge; and         -   P11: Phe -   and pharmaceutically acceptable salts thereof.

In accordance with the present invention these β-hairpin peptidomimetics can be prepared by a process which comprises

(a) coupling an appropriately functionalized solid support with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position 5, 6 or 7, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;

(b) removing the N-protecting group from the product thus obtained;

(c) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position nearer the N-terminal amino acid residue, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;

(d) removing the N-protecting group from the product thus obtained;

(e) repeating steps (c) and (d) until the N-terminal amino acid residue has been introduced;

(f) coupling the product thus obtained with a compound of the general formula

-   -   wherein

is as defined above and X is an N-protecting group or, alternatively, if

is to be group (a1) or (a2), above,

-   -   (fa) coupling the product obtained in step (e) with an         appropriately N-protected derivative of an amino acid of the         general formula         HOOC—B—H III or HOOC-A-H  IV     -   wherein B and A are as defined above, any functional group which         may be present in said N-protected amino acid derivative being         likewise appropriately protected;     -   (fb) removing the N-protecting group from the product thus         obtained; and     -   (fc) coupling the product thus obtained with an appropriately         N-protected derivative of an amino acid of the above general         formula IV and, respectively, III, any functional group which         may be present in said N-protected amino acid derivative being         likewise appropriately protected; and, respectively, if

-   -   is to be group (a3), above,     -   (fa′) coupling the product obtained in step (e) with an         appropriately N-protected derivative of an amino acid of the         above general formula III, any functional group which may be         present in said N-protected amino acid derivative being likewise         appropriately protected;     -   (fb′) removing the N-protecting group from the product thus         obtained; and     -   (fc′) coupling the product thus obtained with an appropriately         N-protected derivative of an amino acid of the above general         formula III, any functional group which may be present in said         N-protected amino acid derivative being likewise appropriately         protected;

(g) removing the N-protecting group from the product obtained in step (f) or (fc) or (fc′);

(h) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position 11, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;

(i) removing the N-protecting group from the product thus obtained;

(j) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position farther away from position 11, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;

(k) removing the N-protecting group from the product thus obtained;

(l) repeating steps (j) and (k) until all amino acid residues have been introduced;

(m) if desired, selectively deprotecting one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated;

(n) if desired, forming an interstrand linkage between side-chains of appropriate amino acid residues at positions 2 and 10;

(o) detaching the product thus obtained from the solid support;

(p) cyclizing the product cleaved from the solid support;

(q) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, if desired, any protecting group(s) which may in addition be present in the molecule; and

(r) if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula I or into a different, pharmaceutically acceptable, salt.

Alternatively, the peptidomimetics of the present invention can be prepared by

(a′) coupling an appropriately functionalized solid support with a compound of the general formula

wherein

is as defined above and X is an N-protecting group or, alternatively, if

is to be group (a1) or (a2), above,

-   -   (a′a) coupling said appropriately functionalized solid support         with an appropriately N-protected derivative of an amino acid of         the general formula         HOOC—B—H III or HOOC-A-H  IV     -   wherein B and A are as defined above, any functional group which         may be present in said N-protected amino acid derivative being         likewise appropriately protected;     -   (a′b) removing the N-protecting group from the product thus         obtained; and     -   (a′c) coupling the product thus obtained with an appropriately         N-protected derivative of an amino acid of the above general         formula IV and, respectively, III, any functional group which         may be present in said N-protected amino acid derivative being         likewise appropriately protected; and, respectively, if

-   -   is to be group (a3), above,     -   (a′a′) coupling said appropriately functionalized solid support         with an appropriately N-protected derivative of an amino acid of         the above general formula III, any functional group which may be         present in said N-protected amino acid derivative being likewise         appropriately protected;     -   (a′b′) removing the N-protecting group from the product thus         obtained; and     -   (a′c′) coupling the product thus obtained with an appropriately         N-protected derivative of an amino acid of the above general         formula III, any functional group which may be present in said         N-protected amino acid derivative being likewise appropriately         protected;

(b′) removing the N-protecting group from the product obtained in step (a′), (a′c) or (a′c′);

(c′) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position 11, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;

(d′) removing the N-protecting group from the product thus obtained;

(e′) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position farther away from position 11, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;

(f′) removing the N-protecting group from the product thus obtained;

(g′) repeating steps (e′) and (f′) until all amino acid residues have been introduced;

(h′) if desired, selectively deprotecting one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated;

(i′) if desired forming an interstrand linkage between side-chains of appropriate amino acid residues at positions 2 and 10;

(j′) detaching the product thus obtained from the solid support;

(k′) cyclizing the product cleaved from the solid support;

(l′) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, if desired, any protecting group(s) which may in addition be present in the molecule; and

(m′) if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula I or into a different, pharmaceutically acceptable, salt.

The peptidomimetics of the present invention can also be enantiomers of the compounds of formula I. These enantiomers can be prepared by a modification of the above processes in which enantiomers of all chiral starting materials are used.

As used in this description, the term “alkyl”, taken alone or in combinations, designates saturated, straight-chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms. Similarly, the term “alkenyl” designates straight chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms and containing at least one or, depending on the chain length, up to four olefinic double bonds. The term “lower” designates radicals and compounds having up to 6 carbon atoms. Thus, for example, the term “lower alkyl” designates saturated, straight-chain or branched hydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl and the like. The term “aryl” designates aromatic carbocyclic hydrocarbon radicals containing one or two six-membered rings, such as phenyl or naphthyl, which may be substituted by up to three substituents such as Br, Cl, F, CF₃, NO₂, lower alkyl or lower alkenyl. The term “heteroaryl” designates aromatic heterocyclic radicals containing one or two five- and/or six-membered rings, at least one of them containing up to three heteroatoms selected from the group consisting of O, S and N and said ring(s) being optionally substituted; representative examples of such optionally substituted heteroaryl radicals are indicated hereinabove in connection with the definition of R⁷⁷.

The structural element -A-CO— designates amino acid building blocks which in combination with the structural element —B—CO— form templates (a1) and (a2). The structural element

—B—CO— forms in combination with another structural element —B—CO— template (a3)_(o)The template (a3) is less preferred in formula I. Templates (a) through (p) constitute building blocks which have an N-terminus and a C-terminus oriented in space in such a way that the distance between those two groups may lie between 4.0-5.5 A. The peptide chain Z is linked to the C-terminus and the N-terminus of the templates (a) through (p) via the corresponding N- and C-termini so that the template and the chain form a cyclic structure such as that depicted in formula I. In a case as here where the distance between the N- and C-termini of the template lies between 4.0-5.5 A the template will induce the H-bond network necessary for the formation of a β-hairpin conformation in the peptide chain Z. Thus template and peptide chain form a β-hairpin mimetic.

The β-hairpin conformation is highly relevant for the serine protease inhibitory activity of the β-hairpin mimetics of the present invention. The β-hairpin stabilizing conformational properties of the templates (a) through (p) play a key role not only for the selective inhibitory activity but also for the synthesis process defined hereinabove, as incorporation of the templates at the beginning or near the middle of the linear protected peptide precursors enhances cyclization yields significantly.

Building blocks A1-A69 belong to a class of amino acids wherein the N-terminus is a secondary amine forming part of a ring. Among the genetically encoded amino acids only proline falls into this class. The configuration of building block A1 through A69 is (D), and they are combined with a building block —B—CO— of (L)-configuration. Preferred combinations for templates (a1) are-^(D)A1-CO—^(L)B—CO— to ^(D)A69-CO—^(L)B—CO—. Thus, for example, ^(D)Pro-^(L)Pro constitutes the prototype of templates (a1). Less preferred, but possible are combinations

-^(L)A1-CO-^(D)B—CO— to -^(L)A69-CO—^(D)B—CO— forming templates (a2)_(o)Thus, for example, ^(L)Pro-^(D)Pro constitutes the prototype of template (a2).

It will be appreciated that building blocks -A1-CO— to -A69-CO— in which A has (D)-configuration, are carrying a group R¹ at the α-position to the N-terminus. The preferred values for R¹ are H and lower alkyl with the most preferred values for R¹ being H and methyl. It will be recognized by those skilled in the art, that A1-A69 are shown in (D)-configuration which, for R¹ being H and methyl, corresponds to the (R)-configuration. Depending on the priority of other values for R¹ according to the Cahn, Ingold and Prelog-rules, this configuration may also have to be expressed as (S).

In addition to R¹ building blocks -A1-CO— to -A69-CO— can carry an additional substituent designated as R² to R¹⁷. This additional substituent can be H, and if it is other than H, it is preferably a small to medium-sized aliphatic or aromatic group. Examples of preferred values for R² to R¹⁷ are:

R²: H; lower alkyl; lower alkenyl; (CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); (CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); (CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: H; or lower alkyl); (CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); (CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁵: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: where H; or lower alkyl); (CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); (CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: alkyl; alkenyl; aryl; and aryl-lower alkyl; heteroaryl-lower alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); (CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); (CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); (CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R₁₀: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R¹¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R¹²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(r)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R¹³: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(r)COO⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or

—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R¹⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R¹⁵: lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); (CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); particularly favoured are NR²⁰COlower alkyl (R²⁰═H; or lower alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);

—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R¹⁶: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R¹⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

Among the building blocks A1 to A69 the following are preferred: A5 with R² being H, A8, A22, A25, A38 with R² being H, A42, A47 and A50. Most preferred are building blocks of type A8′:

wherein R²⁰ is H or lower alkyl; and R⁶⁴ is alkyl; alkenyl; [(CH₂)_(u)—X]_(t)—CH₃, wherein X is —O—, —NR²⁰ or —S—, u is 1-3 and t is 1-6; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl; especially those wherein R⁶⁴ is n-hexyl (A8′-1); n-heptyl (A8′-2); 4-(phenyl)benzyl (A8′-3); diphenylmethyl (A8′-4); 3-amino-propyl (A8′-5); 5-amino-pentyl (A8′-6); methyl (A8′-7); ethyl (A8′-8); isopropyl (A8′-9); isobutyl (A8′-10); n-propyl (A8′-11); cyclohexyl (A8′-12); cyclohexylmethyl (A8′-13); n-butyl (A8′-14); phenyl (A8′-15); benzyl (A8′-16); (3-indolyl)methyl (A8′-17); 2-(3-indolyl)ethyl (A8′-18); (4-phenyl)phenyl (A8′-19); n-nonyl (A8′-20); CH₃—OCH₂CH₂—OCH₂— and CH₃—(OCH₂CH₂)₂—OCH₂—.

Building block A70 belongs to the class of open-chain α-substituted α-amino acids, building blocks A71 and A72 to the corresponding β-amino acid analogues and building blocks A73-A104 to the cyclic analogues of A70. Such amino acid derivatives have been shown to constrain small peptides in well defined reverse turn or U-shaped conformations (C. M. Venkatachalam, Biopolymers, 1968, 6, 1425-1434; W. Kabsch, C Sander, Biopolymers 1983, 22, 2577)_(o)Such building blocks or templates are ideally suited for the stabilization of β-hairpin conformations in peptide loops (D. Obrecht, M. Altorfer, J. A. Robinson, “Novel Peptide Mimetic Building Blocks and Strategies for Efficient Lead Finding”, Adv. Med Chem. 1999, Vol. 4, 1-68; P. Balaram, “Non-standard amino acids in peptide design and protein engineering”, Curr. Opin. Struct. Biol. 1992, 2, 845-851; M. Crisma, G. Valle, C. Toniolo, S. Prasad, R. B. Rao, P. Balaram, “β-turn conformations in crystal structures of model peptides containing α,α-disubstituted amino acids”, Biopolymers 1995, 35, 1-9; V. J. Hruby, F. Al-Obeidi, W. Kazmierski, Biochem. J. 1990, 268, 249-262).

It has been shown that both enantiomers of building blocks -A70-CO— to A104-CO— in combination with a building block —B—CO— of L-configuration can efficiently stabilize and induce β-hairpin conformations (D. Obrecht, M. Altorfer, J. A. Robinson, “Novel Peptide Mimetic Building Blocks and Strategies for Efficient Lead Finding”, Adv. Med Chem. 1999, Vol. 4, 1-68; D. Obrecht, C. Spiegler, P. Schönholzer, K. Müller, H. Heimgartner, F. Stierli, Helv. Chim. Acta 1992, 75, 1666-1696; D. Obrecht, U. Bohdal, J. Daly, C. Lehmann, P. Schönholzer, K. Müller, Tetrahedron 1995, 51, 10883-10900; D. Obrecht, C. Lehmann, C. Ruffieux, P. Schonholzer, K. Müller, Helv. Chim. Acta 1995, 78, 1567-1587; D. Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P. Schönholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D. Obrecht, H. Karajiannis, C. Lehmann, P. Schönholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 703-714).

Thus, for the purposes of the present invention templates (a1) can also consist of -A70-CO— to A104-CO— where building block A70 to A104 is of either (D)- or (L)-configuration, in combination with a building block —B—CO— of (L)-configuration.

Preferred values for R²⁰ in A70 to A104 are H or lower alkyl with methyl being most preferred. Preferred values for R¹⁸, R¹⁹ and R²¹ to R²⁹ in building blocks A70 to A104 are the following:

-   -   R¹⁸: lower alkyl.     -   R¹⁹: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(p)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R²¹: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(p)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or (CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R²²: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF; lower alkyl; lower alkenyl; or lower alkoxy).

R²³: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); particularly favoured are NR²⁰COlower alkyl (R²⁰═H; or lower alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);

—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy);

R²⁴: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); particularly favoured are NR²⁰COlower alkyl (R²⁰═H; or lower alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);

—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy);

R²⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R²⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;

—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

Alternatively, R²⁵ and R²⁶ taken together can be —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).

R²⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁸ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R²⁸: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁸⁸ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁸ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R²⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); particularly favored are NR²⁰COlower-alkyl (R²⁰═H; or lower alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);

—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

The preferred value for R²³, R²⁴ and R²⁹ is —NR²⁰—CO-lower alkyl where R²⁰ is H or lower alkyl.

For templates (b) to (p), such as (b1) and (1), the preferred values for the various symbols are the following:

R¹: H; or lower Alkyl;

R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R²⁰: H; or lower alkyl.

R³⁰: H, methyl.

R³¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); (—CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); most preferred is —CH₂CONR⁵⁸R⁵⁹ (R⁵⁸: H; or lower alkyl; R⁵⁹: lower alkyl; or lower alkenyl).

R³²: H, methyl.

R³³: lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³⁴R⁶³ (where R³⁴: lower alkyl; or lower alkenyl; R⁶³: H; or lower alkyl; or R³⁴ and R⁶³ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); (CH₂)_(m)OCONR⁷⁵R⁸² (where R⁷⁵: lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R⁷⁵ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(o)NR²⁰CONR⁷⁸R⁸² (where R²⁰: H; or lower lower alkyl; R⁷⁸: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R⁷⁸ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).

R³⁴: H; or lower alkyl.

R³⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;

—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).

R³⁶: lower alkyl; lower alkenyl; or aryl-lower alkyl.

R³⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alky; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R³⁸: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁸ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R³⁹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).

R⁴⁰: lower alkyl; lower alkenyl; or aryl-lower alkyl.

R⁴¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;

—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alky; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁴²: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;

—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁴³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁴⁴: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁸ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁴⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁴⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(s)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(s)SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(s)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(r)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(s)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁴⁷: H; or OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl).

R⁴⁸: H; or lower alkyl.

R⁴⁹: H; lower alkyl; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or (CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁵⁰: H; methyl.

R⁵¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); (CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;

—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁵²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;

—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁵³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;

—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁵⁴: lower alkyl; lower alkenyl; or aryl-lower alkyl.

Most preferably R¹ is H; R²⁰ is H; R³⁰ is H; R³¹ is carboxymethyl; or lower alkoxycarbonylmethyl; R³² is H; R³⁵ is methyl; R³⁶ is methoxy; R³⁷ is H and R³⁸ is H.

Among the building blocks A70 to A104 the following are preferred: A74 with R²² being H, A75, A76, A77 with R²² being H, A78 and A79.

The building block —B—CO— within templates (a1), (a2) and (a3) designates an L-amino acid residue. Preferred values for B are: —NR²⁰CH(R⁷¹)— and enantiomers of groups A5 with R² being H, A8, A22, A25, A38 with R² being H, A42, A47, and A50. Most preferred are

Ala L-Alanine Arg L-Arginine Asn L-Asparagine Cys L-Cysteine Gln L-Glutamine Gly Glycine His L-Histidine Ile L-Isoleucine Leu L-Leucine Lys L-Lysine Met L-Methionine Phe L-Phenylalanine Pro L-Proline Pro(5RPhe) (2S,5R)-5-phenylpyrrrolidine-2-carbocyclic acid Ser L-Serine Thr L-Threonine Trp L-Tryptophan Tyr L-Tyrosine Val L-Valine Cit L-Citrulline Orn L-Ornithine tBuA L-t-Butylalanine Sar Sarcosine t-BuG L-tert.-Butylglycine 4AmPhe L-para-Aminophenylalanine 3AmPhe L-meta-Aminophenylalanine 2AmPhe L-ortho-Aminophenylalanine Phe(mC(NH₂)═NH) L-meta-Amidinophenylalanine Phe(pC(NH₂)═NH) L-para-Amidinophenylalanine Phe(mNHC (NH₂)═NH) L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH) L-para-Guanidinophenylalanine Phg L-Phenylglycine Cha L-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅al L-3-Cyclopentylalanine Nle L-Norleucine 2-Nal L-2-Naphthylalanine 1-Nal L-1-Naphthylalanine 4Cl-Phe L-4-Chlorophenylalanine 3Cl-Phe L-3-Chlorophenylalanine 2Cl-Phe L-2-Chlorophenylalanine 3,4Cl₂₋Phe L-3,4-Dichlorophenylalanine 4F-Phe L-4-Fluorophenylalanine 3F-Phe L-3-Fluorophenylalanine 2F-Phe L-2-Fluorophenylalanine Tic L-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid Thi L-β-2-Thienylalanine Tza L-2-Thiazolylalanine Mso L-Methionine sulfoxide AcLys L-N-Acetyllysine Dpr L-2,3-Diaminopropionic acid A₂Bu L-2,4-Diaminobutyric acid Dbu (S)-2,3-Diaminobutyric acid Abu γ-Aminobutyric acid (GABA) Aha ε-Aminohexanoic acid Aib α-Aminoisobutyric acid Y(Bzl) L-O-Benzyltyrosine Bip L-Biphenylalanine S(Bzl) L-O-Benzylserine T(Bzl) L-O-Benzylthreonine hCha L-Homo-cyclohexylalanine hCys L-Homo-cysteine hSer L-Homo-serine hArg L-Homo-arginine hPhe L-Homo-phenylalanine Bpa L-4-Benzoylphenylalanine Pip L-Pipecolic acid OctG L-Octylglycine MePhe L-N-Methylphenylalanine MeNle L-N-Methylnorleucine MeAla L-N-Methylalanine MeIle L-N-Methylisoleucine MeVal L-N-Methvaline MeLeu L-N-Methylleucine

In addition, the most preferred values for B also include groups of type A8″ of (L)-configuration:

-   -   wherein R²⁰ is H or lower alkyl and R⁶⁴ is alkyl; alkenyl;         —[(CH₂)_(u)—X]_(t)—CH₃ (where X is     -   —O—; —NR²⁰—, or —S—, u is 1-3 and t is 1-6), aryl; aryl-lower         alkyl; or heteroaryl-lower alkyl; especially those wherein R⁶⁴         is n-hexyl (A8″-21); n-heptyl (A8″-22); n-(phenyl)benzyl         (A8″-23); diphenylmethyl (A8″-24); 3-amino-propyl (A8″-25);         5-amino-pentyl (A8″-26); methyl (A8″-27); ethyl (A8″-28);         isopropyl (A8″-29); isobutyl (A8″-30); n-propyl (A8″-31);         cyclohexyl (A8″-32); cyclohexylmethyl (A8″-33); n-butyl         (A8″-34); phenyl (A8″-35); benzyl (A8″-36); (3-indolyl)methyl         (A8″-37); 2-(3-indolyl)ethyl (A8″-38); (4-phenyl)phenyl         (A8″-39); n-nonyl (A8″-40); CH₃—OCH₂CH₂—OCH₂— (A8″-41) and         CH₃—(OCH₂CH₂)₂—OCH₂— (A8″-42).

The peptidic chain Z of the β-hairpin mimetics described herein is generally defined in terms of amino acid residues belonging to one of the following groups:

-   -   Group C —NR²⁰CH(R⁷²)CO—; “hydrophobic: small to medium-sized”     -   Group D —NR²⁰CH(R⁷³)CO—; “hydrophobic: large aromatic or         heteroaromatic”     -   Group E —NR²⁰CH(R⁷⁴)CO—; “polar-cationic” and “urea-derived”     -   Group F —NR²⁰CH(R⁸⁴)CO—; “polar-non-charged or anionic”     -   Group H —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;         —NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰—;         —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; and         —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—;         “interstrand linkage”

Furthermore, the amino acid residues in chain Z can also be of formula -A-CO— or of formula —B—CO— wherein A and B are as defined above. Finally, Gly can also be an amino acid residue in chain Z, and Pro and Pro(4-NHCOPhe) can be amino acid residues in chain Z, too, with the exception of positions where an interstrand linkage (H) is possible.

Group C comprises amino acid residues with small to medium-sized hydrophobic side chain groups according to the general definition for substituent R⁷². A hydrophobic residue refers to an amino acid side chain that is uncharged at physiological pH and that is repelled by aqueous solution. Furthermore these side chains generally do not contain hydrogen bond donor groups, such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas. However, they may contain hydrogen bond acceptor groups such as ethers, thioethers, esters, tertiary amides, alkyl- or aryl phosphonates and phosphates, or tertiary amines. Genetically encoded small-to-medium-sized amino acids include alanine, isoleucine, leucine, methionine and valine.

Group D comprises amino acid residues with aromatic and heteroaromatic side chain groups according to the general definition for substituent R⁷³. An aromatic amino acid residue refers to a hydrophobic amino acid having a side chain containing at least one ring having a conjugated π-electron system (aromatic group). In addition they may contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, tertiary amides, alkyl- or aryl phosphonates and phosphates, or tertiary amines Genetically encoded aromatic amino acids include phenylalanine and tyrosine.

A heteroaromatic amino acid residue refers to a hydrophobic amino acid having a side chain containing at least one ring having a conjugated π-system incorporating at least one heteroatom such as (but not limited to) O, S and N according to the general definition for substituent R⁷⁷. In addition such residues may contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, tertiary amides, alkyl- or aryl phosphonates and phosphates, or tertiary amines Genetically encoded heteroaromatic amino acids include tryptophan and histidine.

Group E comprises amino acids containing side chains with polar-cationic, acylamino- and urea-derived residues according to the general definition for substituent R⁷⁴. Polar-cationic refers to a basic side chain which is protonated at physiological pH. Genetically encoded polar-cationic amino acids include arginine, lysine and histidine. Citrulline is an example for an urea derived amino acid residue.

Group F comprises amino acids containing side chains with polar-non-charged or anionic residues according to the general definition for substituent R⁸⁴. A polar-non-charged or anionic residue refers to a hydrophilic side chain that is uncharged and, respectively anionic at physiological pH (carboxylic acids being included), but that is not repelled by aqueous solutions. Such side chains typically contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, carboxylic acids and esters, primary and secondary amines, thiols, alcohols, phosphonates, phosphates, ureas or thioureas. These groups can form hydrogen bond networks with water molecules. In addition they may also contain hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, tertiary amides, carboxylic acids and carboxylates, alkyl- or aryl phosphonates and phosphates, or tertiary amines. Genetically encoded polar-non-charged amino acids include asparagine, cysteine, glutamine, serine and threonine, but also aspartic acid and glutamic acid.

Group H comprises side chains of preferably (L)-amino acids at opposite positions of the β-strand region that can form an interstrand linkage. The most widely known linkage is the disulfide bridge formed by cysteines and homo-cysteines positioned at opposite positions of the β-strand. Various methods are known to form disulfide linkages including those described by: J. P. Tam et al. Synthesis 1979, 955-957; Stewart et al., Solid Phase Peptide Synthesis, 2d Ed., Pierce Chemical Company, III., 1984; Ahmed et al. J. Biol. Chem. 1975, 250, 8477-8482; and Pennington et al., Peptides, pages 164-166, Giralt and Andreu, Eds., ESCOM Leiden, The Netherlands, 1990. Most advantageously, for the scope of the present invention, disulfide linkages can be prepared using acetamidomethyl (Acm)-protective groups for cysteine. A well established interstrand linkage consists in linking ornithines and lysines, respectively, with glutamic and aspartic acid residues located at opposite β-strand positions by means of an amide bond formation. Preferred protective groups for the side chain amino-groups of ornithine and lysine are allyloxycarbonyl (Alloc) and allylesters for aspartic and glutamic acid. Finally, interstrand linkages can also be established by linking the amino groups of lysine and ornithine located at opposite β-strand positions with reagents such as N,N-carbonylimidazole to form cyclic ureas.

As mentioned earlier, positions for an interstrand linkage are positions P2 and 10, taken together. Such interstrand linkages are known to stabilize the β-hairpin conformations and thus constitute an important structural element for the design of β-hairpin mimetics.

Most preferred amino acid residues in chain Z are those derived from natural α-amino acids. Hereinafter follows a list of amino acids which, or the residues of which, are suitable for the purposes of the present invention, the abbreviations corresponding to generally adopted usual practice:

three letter code one letter code Ala L-Alanine A Arg L-Arginine R Asn L-Asparagine N Asp L-Aspartic acid D Cys L-Cysteine C Glu L-Glutamic acid E Gln L-Glutamine Q Gly Glycine G His L-Histidine H Ile L-Isoleucine I Leu L-Leucine L Lys L-Lysine K Met L-Methionine M Phe L-Phenylalanine F Pro L-Proline P ^(D)Pro D-Proline ^(D)P Ser L-Serine S Thr L-Threonine T Trp L-Tryptophan W Tyr L-Tyrosine Y Val L-Valine V

Other α-amino acids which, or the residues of which, are suitable for the purposes of the present invention include:

Cit L-Citrulline Orn L-Ornithine tBuA L-t-Butylalanine Sar Sarcosine Pen L-Penicillamine t-BuG L-tert.-Butylglycine 4AmPhe L-para-Aminophenylalanine 3AmPhe L-meta-Aminophenylalanine 2AmPhe L-ortho-Aminophenylalanine Phe(mC(NH₂)═NH) L-meta-Amidinophenylalanine Phe(pC(NH₂)═NH) L-para-Amidinophenylalanine Phe(mNHC (NH₂)═NH) L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH) L-para-Guanidinophenylalanine Phg L-Phenylglycine Cha L-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅al L-3-Cyclopentylalanine Nle L-Norleucine 2-Nal L-2-Naphthylalanine 1-Nal L-1-Naphthylalanine 4Cl-Phe L-4-Chlorophenylalanine 3Cl-Phe L-3-Chlorophenylalanine 2Cl-Phe L-2-Chlorophenylalanine 3,4Cl₂-Phe L-3,4-Dichlorophenylalanine 4F-Phe L-4-Fluorophenylalanine 3F-Phe L-3-Fluorophenylalanine 2F-Phe L-2-Fluorophenylalanine Tic 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid Thi L-β-2-Thienylalanine Tza L-2-Thiazolylalanine Mso L-Methionine sulfoxide AcLys N-Acetyllysine Dpr 2,3-Diaminopropionic acid A₂Bu 2,4-Diaminobutyric acid Dbu (S)-2,3-Diaminobutyric acid Abu γ-Aminobutyric acid (GABA) Aha ε-Aminohexanoic acid Aib α-Aminoisobutyric acid Y(Bzl) L-O-Benzyltyrosine Bip L-(4-phenyl)phenylalanine S(Bzl) L-O-Benzylserine T(Bzl) L-O-Benzylthreonine hCha L-Homo-cyclohexylalanine hCys L-Homo-cysteine hSer L-Homo-serine hArg L-Homo-arginine hPhe L-Homo-phenylalanine Bpa L-4-Benzoylphenylalanine 4-AmPyrr1 (2S,4S)-4-Amino-pyrrolidine-L-carboxylic acid 4-AmPyrr2 (2S,4R)-4-Amino-pyrrolidine-L-carboxylic acid 4-PhePyrr1 (2S,5R)-4-Phenyl-pyrrolidine-L-carboxylic acid 4-PhePyrr2 (2S,5S)-4-Phenyl-pyrrolidine-L-carboxylic acid 5-PhePyrr1 (2S,5R)-5-Phenyl-pyrrolidine-L-carboxylic acid 5-PhePyrr2 (2S,5S)-5-Phenyl-pyrrolidine-L-carboxylic acid Pro(4-OH)1 (4S)-L-Hydroxyproline Pro(4-OH)2 (4R)-L-Hydroxyproline Pip L-Pipecolic acid ^(D)Pip D-Pipecolic acid OctG L-Octylglycine NGly N-Methylglycine MePhe L-N-Methylphenylalanine MeNle L-N-Methylnorleucine MeAla L-N-Methylalanine MeIle L-N-Methylisoleucine MeVal L-N-Methylvaline MeLeu L-N-Methylleucine DimK L-(N′,N′Dimethyl)-lysine Lpzp L-Piperazinic acid Dpzp D-Piperazinic acid Isorn L-(N′,N′-diisobutyl)-ornithine PipAla L-2-(4′-piperidinyl)-alanine PirrAla L-2-(3′-pyrrolidinyl)-alanine Ampc 4-Amino-piperidine-4-carboxylic acid NMeR L-N-Methylarginine NMeK L-N-Methyllysine NMePhe L-N-Methylphenylalanine IPegK L-2-Amino-6-{2-[2-(2-methoxy- ethoxy)ethoxy]acetylamino}-hexanoic acid SPegK L-2-Amino-6-[2-(2methoxy-ethoxy)- acetylamino]-hexanoic acid Dab L-2,4-Diamino-butyric acid IPegDab L-2-Amino-4{2-[2-(2-methoxy-ethoxy)- ethoxy]-acetylamino}-butyric acid SPegDab L-2-Amino-4[2-(2-methoxy-ethoxy)- acetylamino] butyric acid 4-PyrAla L-2-(4′Pyridyl)-alanine OrnPyr L-2-Amino-5-[(2′carbonylpyrazine)]amino- pentanoic acid BnG N-Benzylglycine AlloT Allo-Threonin Pro(4NHCOPhe) (2S)-4-benzamidino-pyrrolidine-2-carboxylic acid Aoc 2-(S)-Aminooctanoic acid

Particularly preferred residues for group C are:

Ala L-Alanine Ile L-Isoleucine Leu L-Leucine Met L-Methionine Val L-Valine tBuA L-t-Butylalanine t-BuG L-tert.-Butylglycine Cha L-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅al L-3-Cyclopentylalanine Nle L-Norleucine hCha L-Homo-cyclohexylalanine OctG L-Octylglycine MePhe L-N-Methylphenylalanine MeNle L-N-Methylnorleucine MeAla L-N-Methylalanine MeIle L-N-Methylisoleucine MeVal L-N-Methylvaline MeLeu L-N-Methylleucine Aoc 2-(S)-Aminooctanoic acid

Particularly preferred residues for group D are:

His L-Histidine Phe L-Phenylalanine Trp L-Tryptophan Tyr L-Tyrosine Phg L-Phenylglycine 2-Nal L-2-Naphthylalanine 1-Nal L-1-Naphthylalanine 4Cl-Phe L-4-Chlorophenylalanine 3Cl-Phe L-3-Chlorophenylalanine 2Cl-Phe L-2-Chlorophenylalanine 3,4Cl₂-Phe L-3,4-Dichlorophenylalanine 4F-Phe L-4-Fluorophenylalanine 3F-Phe L-3-Fluorophenylalanine 2F-Phe L-2-Fluorophenylalanine Thi L-β-2-Thienylalanine Tza L-2-Thiazolylalanine Y(Bzl) L-O-Benzyltyrosine Bip L-Biphenylalanine S(Bzl) L-O-Benzylserine T(Bzl) L-O-Benzylthreonine hPhe L-Homo-phenylalanine Bpa L-4-Benzoylphenylalanine PirrAla L-2-(3′-pyrrolidinyl)-alanine NMePhe L-N-Methylphenylalanine 4-PyrAla L-2-(4′Pyridyl)-alanine

Particularly preferred residues for group E are

Arg L-Arginine Lys L-Lysine Orn L-Ornithine Dpr L-2,3-Diaminopropionic acid A₂Bu L-2,4-Diaminobutyric acid Dbu (S)-2,3-Diaminobutyric acid Phe(pNH₂) L-para-Aminophenylalanine Phe(mNH₂) L-meta-Aminophenylalanine Phe(oNH₂) L-ortho-Aminophenylalanine hArg L-Homo-arginine Phe(mC(NH₂)═NH) L-meta-Amidinophenylalanine Phe(pC(NH₂)═NH) L-para-Amidinophenylalanine Phe(mNHC (NH₂)═NH) L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH) L-para-Guanidinophenylalanine DimK L-(N′,N′Dimethyl)-lysine Isorn L-(N′,N′-diisobutyl)-ornithine NMeR L-N-Methylarginine NMeK L-N-Methyllysine IPegK L-2-Amino-6-{2-[2-(2-methoxy- ethoxy)ethoxy]acetylamino}-hexanoic acid SPegK L-2-Amino-6-[2-(2methoxy-ethoxy)- acetylamino]-hexanoic acid Dab L-2,4-Diamino-butyric acid IPegDab L-2-Amino-4{2-[2-(2-methoxy-ethoxy)- ethoxy]-acetylamino}-butyric acid SPegDab L-2-Amino-4[2-(2-methoxy-ethoxy)- acetylamino] butyric acid OrnPyr L-2-Amino-5-[(2′carbonylpyrazine)]amino- pentanoic PipAla L-2-(4′-piperidinyl)-alanine

Particularly preferred residues for group F are

Asn L-Asparagine Asp L-Aspartic acid Cys L-Cysteine Gln L-Glutamine Glu L-Glutamic acid Ser L-Serine Thr L-Threonine AlloThr Allo Threonine Cit L-Citrulline Pen L-Penicillamine AcLys L-N^(ε)-Acetyllysine hCys L-Homo-cysteine hSer L-Homo-serine

Generally, the peptidic chain Z within the β-hairpin mimetics of the invention comprises 11 amino acid residues. The positions P1 to P11 of each amino acid residue in the chain Z are unequivocally defined as follows: P1 represents the first amino acid in the chain Z that is coupled with its N-terminus to the C-terminus of the templates (b)-(p), or of group —B—CO— in template (a1), or of group -A-CO— in template (a2), or of the group —B—CO— forming the C-terminus of template (a3); and P11 represents the last amino acid in the chain Z that is coupled with its C-terminus to the N-terminus of the templates (b)-(p), or of group -A-CO— in template (a1), or of group —B—CO— in template (a2), or of the group —B—CO— forming the N-terminus of template (a3)_(o)Each of the positions P1 to P11 will preferably contain an amino acid residue belonging to one of the above types C, D, E, F, H, or of formula -A-CO— or of formula —B—CO—, or being Gly, Pro or Pro(4NHCOPhe) as follows:

In general the α-amino acid residues in positions 1 to 11 of the chain Z are preferably:

-   -   P1: of type C, or of type D, or of type E, or of type F;     -   P2: of type E, or of type F, or of type C;     -   P3: or of type C, of type F or the residue is Gly;     -   P4: of type C, or of type E, or of type F, or the residue is Gly         or Pro;     -   P5: of type E, or of type F, or the residue is Gly or Pro;     -   P6: of type C, or of type D, or of type F, or the residue is Gly         or Pro;     -   P7: of type F or of formula -A-CO— or the residue is Gly or Pro;     -   P8: of type D, or of type C, or of formula -A-CO or the residue         is Gly or Pro or Pro(4NHCOPhe);     -   P9: of type C, or of type D, or of type E, or of type F;     -   P10: of type F, or of type C, or type E;     -   P11: of type E, or of type F, or of type C or of type D; or     -   P2 and P10, taken together, form a group of type H;

with the proviso that if template is ^(D)Pro-^(L)Pro the amino acid residues in positions P1 to P11 are other than

-   -   P1: Arg     -   P2: Cys, linked with Cys in position P10 by a disulfide bridge     -   P3: Thr     -   P4 Lys     -   P5 Ser     -   P6 Ile     -   P7 Pro     -   P8 Pro     -   P9 Ile     -   P10 Cys, linked with Cys in position P2 by a disulfide bridge;         and     -   P11 Phe.

The α-amino acid residues in positions 1 to 11 are most preferably:

-   -   P1: Nle, Ile, Aoc, hLeu, Chg, OctG, hPhe, 4AmPhe, Cha, Phe, Tyr,         2Cl-Phe, Trp, 1-Nal, Leu, Cha, or Arg;     -   P2: Cys, Glu, Nle, Thr, or Gln;     -   P3: Thr, Ala or Abu;     -   P4: Lys, Nle, Ala, Abu, or Thr;     -   P5: Ser, AlloThr, or Dpr;     -   P6: Ile, Csal, Leu, Nle, Aoc, OctG, Cha, hLeu, hPhe, Chg, t-BuA,         Glu, or Asp;     -   P7: Pro;     -   P8: Pro, Ala, or Pro(4NHCOPhe);     -   P9: Tyr, Phe, Ile, Nle, Cha, Gln, Arg, Lys, His, Thr, or Ala;     -   P10: Cys, Arg, Nle, Gln, Lys, Met, Thr, or Ser;     -   P11: Tyr, Gln, Arg, Ser, Nle, 2-Nal, 2Cl-Phe, Cha, Phg, Tyr,         Phe, Asp, Asn, or Thr; and     -   Cys, if present at P2 and P10, may form a disulfide bridge.

For inhibitors of Cathepsin G the α-amino acid residues in positions 1 to 11 of the chain Z are preferably:

-   -   P1: of type C, or of type D, or of type E;     -   P2: of type F, or of type C;     -   P3: of type F;     -   P4: of type C, or of type E;     -   P5: of type E, or of type F;     -   P6: of type F;     -   P7: of type F, or of formula -A-CO—, or the residue is Gly or         Pro;     -   P8: of type C, or of formula -A-CO—, or the residue is Gly or         Pro or     -   Pro(4NHCOPhe);     -   P9: of type C, or of type D, or of type F;     -   P10: of type F, or of type C, or type E;     -   P11: of type E, or of type D, or of type F; or     -   P2 and P10, taken together, form a group of type H.

For inhibitors of Cathepsin G, the α-amino acid residues in positions 1 to 11 are most preferably

-   -   P1: Phe, hPhe, 4AmPhe, Nle, Chg, Ile, Tyr, Arg, Trp, 2Cl-Phe,         Arg, 1-Nal, or Cha;     -   P2: Cys, Glu, or Nle;     -   P3: Thr;     -   P4: Lys, or Nle;     -   P5: Ser, AlloThr, or Dpr;     -   P6: Asp, or Glu;     -   P7: Pro;     -   P8: Pro;     -   P9: Ile, Nle, Cha, Gln, Tyr, or Ala;     -   P10: Cys, Arg, or Nle;     -   P11: Thr, Asp, Ser, Tyr, Phe, Asn, or Arg; and     -   Cys, if present at P2 and P10, may form a disulfide bridge.

For inhibitors of Elastase the α-amino acid residues in positions 1 to 11 of the chain Z are preferably

-   -   P1: of type C, or of type D;     -   P2: of type F;     -   P3: of type For of type C;     -   P4: of type C or of type F;     -   P5: of type F;     -   P6: of type C;     -   P7: of formula -A-CO— or the residue is Gly or Pro;     -   P8: of formula -A-CO or the residue is Gly or Pro or         Pro(4NHCOPhe);     -   P9: of type D, or of type F or of type C;     -   P10: of type F, or of type C, or type E;     -   P11: of type E, or of type F, or of type D; or     -   P2 and P10, taken together, form a group of type H.

For inhibitors of Elastase, the α-amino acid residues in positions 1 to 11 are most preferably:

-   -   P1: Ile, Nle, Aoc, hLeu, Chg, OctG, or hPhe;     -   P2: Cys, Glu, Thr, or Gln;     -   P3: Thr, Ala, or Abu;     -   P4: Ala, Thr, or Abu;     -   P5: Ser;     -   P6: OctG, Ile, Cha, Leu, C₅al, Nle, Aoc, Chg, tBuA, or hLeu;     -   P7: Pro;     -   P8: Pro, or Pro(4NHCOPhe);     -   P9: Gln, Tyr, ILe, or Phe;     -   P10: Cys, Lys, Gln, Thr, Met, or Arg;     -   P11: Tyr, Ser, Arg, Gln, Nle, 2-Nal, 2Cl-Phe, Phe, Cha, or Phg;         and     -   Cys, if present at P2 and P10, may form a disulfide bridge.

For inhibitors of Tryptase the α-amino acid residues in positions 1 to 11 of the chain Z are preferably:

-   -   P1: of type C, or of type D, or of type E;     -   P2: of type F;     -   P3: of type F;     -   P4: of type E;     -   P5: of type F;     -   P6: of type C, or of type D;     -   P7: of type F, or of formula -A-CO—, or the residue is Gly or         Pro;     -   P8: of type C, or of formula -A-CO—, or the residue is Gly or         Pro;     -   P9: of type C, or of type E, or of type F;     -   P10: of type F;     -   P11: of type E, or of type D; or     -   P2 and P10, taken together, form a group of type H; with the         proviso that if the template is ^(D)Pro-^(L)Pro, the amino acid         residues in positions P1 to P11 are other than     -   P1: Arg     -   P2: Cys, linked with Cys in position P10 by a disulfide bridge     -   P3: Thr     -   P4 Lys     -   P5 Ser     -   P6 Ile     -   P7 Pro     -   P8 Pro     -   P9 Ile     -   P10 Cys, linked with Cys in position P10 by a disulfide bridge;         and P11 Phe.

For inhibitors of Tryptase the α-amino acid residues in positions 1 to 11 of the chain Z are most preferably:

-   -   P1: Cha, Tyr, or Trp     -   P2: Cys     -   P3: Thr     -   P4: Lys     -   P5: Ser     -   P6: Leu     -   P7: Pro     -   P8: Pro     -   P9: Lys     -   P10: Cys     -   P11: Arg; and

the Cys residues present at P2 and P10 may form a disulfide bridge.

Particularly preferred β-peptidomimetics of the invention include those described in Examples 5, 19, 20, 22, 23, 38, 39, 40, and 75 as inhibitors of cathepsin G; Examples 91, 121, 153, 154, 155, 156, 157, 158, 159, 160, 161 177, and 178 as inhibitors of elastase; and Examples 193, 194, and 195 as inhibitors of Tryptase.

The processes of the invention can advantageously be carried out as parallel array syntheses to yield libraries of template-fixed β-hairpin peptidomimetics of the above general formula I. Such parallel syntheses allow one to obtain arrays of numerous (normally 24 to 192, typically 96) compounds of general formula I in high yields and defined purities, minimizing the formation of dimeric and polymeric by-products. The proper choice of the functionalized solid-support (i.e. solid support plus linker molecule), templates and site of cyclization play thereby key roles.

The functionalized solid support is conveniently derived from polystyrene crosslinked with, preferably 1-5%, divinylbenzene; polystyrene coated with polyethyleneglycol spacers (Tentagel^(R)); and polyacrylamide resins (see also Obrecht, D.; Villalgordo, J.-M, “Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries”, Tetrahedron Organic Chemistry Series, Vol. 17, Pergamon, Elsevier Science, 1998).

The solid support is functionalized by means of a linker, i.e. a bifunctional spacer molecule which contains on one end an anchoring group for attachment to the solid support and on the other end a selectively cleavable functional group used for the subsequent chemical transformations and cleavage procedures. For the purposes of the present invention two types of linkers are used:

Type 1 linkers are designed to release the amide group under acidic conditions (Rink H, Tetrahedron Lett. 1987, 28, 3783-3790). Linkers of this kind form amides of the carboxyl group of the amino acids; examples of resins functionalized by such linker structures include 4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido) aminomethyl] PS resin, 4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido) aminomethyl]-4-methylbenzydrylamine PS resin (Rink amide MBHA PS Resin), and 4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl]phenoxyacetamido) aminomethyl)benzhydrylamine PS-resin (Rink amide BHA PS resin). Preferably, the support is derived from polystyrene crosslinked with, most preferably 1-5%, divinylbenzene and functionalized by means of the 4-(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido) linker

Type 2 linkers are designed to eventually release the carboxyl group under acidic conditions. Linkers of this kind form acid-labile esters with the carboxyl group of the amino acids, usually acid-labile benzyl, benzhydryl and trityl esters; examples of such linker structures include 2-methoxy-4-hydroxymethylphenoxy (Sasrin^(R) linker), 4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy (Rink linker), 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB linker), trityl and 2-chlorotrityl. Preferably, the support is derived from polystyrene crosslinked with, most preferably 1-5%, divinylbenzene and functionalized by means of the 2-chlorotrityl linker.

When carried out as parallel array syntheses the processes of the invention can be advantageously carried out as described herein below but it will be immediately apparent to those skilled in the art how these procedures will have to be modified in case it is desired to synthesize one single compound of the above formula I.

A number of reaction vessels (normally 24 to 192, typically 96) equal to the total number of compounds to be synthesized by the parallel method are loaded with 25 to 1000 mg, preferably 100 mg, of the appropriate functionalized solid support which is preferably derived from polystyrene cross-linked with 1 to 3% of divinylbenzene, or from Tentagel resin.

The solvent to be used must be capable of swelling the resin and includes, but is not limited to, dichloromethane (DCM), dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene, tetrahydrofuran (THF), ethanol (EtOH), trifluoroethanol (TFE), isopropylalcohol and the like. Solvent mixtures containing as at least one component a polar solvent (e.g. 20% TFE/DCM, 35% THF/NMP) are beneficial for ensuring high reactivity and solvation of the resin-bound peptide chains (Fields, G. B., Fields, C. G., J. Am. Chem. Soc. 1991, 113, 4202-4207).

With the development of various linkers that release the C-terminal carboxylic acid group under mild acidic conditions, not affecting acid-labile groups protecting functional groups in the side chain(s), considerable progresses have been made in the synthesis of protected peptide fragments. The 2-methoxy-4-hydroxybenzylalcohol-derived linker (Sasrin^(R) linker, Mergler et al., Tetrahedron Lett. 1988, 29 4005-4008) is cleavable with diluted trifluoroacetic acid (0.5-1% TFA in DCM) and is stable to Fmoc deprotection conditions during the peptide synthesis, Boc/tBu-based additional protecting groups being compatible with this protection scheme. Other linkers which are suitable for the processes of the invention include the super acid labile 4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy linker (Rink linker, Rink, H Tetrahedron Lett. 1987, 28, 3787-3790), where the removal of the peptide requires 10% acetic acid in DCM or 0.2% trifluoroacetic acid in DCM; the 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid-derived linker (HMPB-linker, Florsheimer & Riniker, Peptides 1991, 1990 131) which is also cleaved with 1% TFA/DCM in order to yield a peptide fragment containing all acid labile side-chain protective groups; and, in addition, the 2-chlorotritylchloride linker (Barbs et al., Tetrahedron Lett. 1989, 30, 3943-3946), which allows the peptide detachment using a mixture of glacial acetic acid/trifluoroethanol/DCM (1:2:7) for 30 min.

Suitable protecting groups for amino acids and, respectively, for their residues are, for example,

-   -   for the amino group (as is present e.g. also in the side-chain         of lysine)

Cbz benzyloxycarbonyl Boc tert.-butyloxycarbonyl Fmoc 9-fluorenylmethoxycarbonyl Alloc allyloxycarbonyl Teoc trimethylsilylethoxycarbonyl Tcc trichloroethoxycarbonyl Nps o-nitrophenylsulfonyl; Trt triphenymethyl or trityl

-   -   for the carboxyl group (as is present e.g. also in the         side-chain of aspartic and glutamic acid) by conversion into         esters with the alcohol components

tBu tert.-butyl Bn benzyl Me methyl Ph phenyl Pac Phenacyl Allyl Tse trimethylsilylethyl Tce trichloroethyl;

-   -   for the guanidino group (as is present e.g. in the side-chain of         arginine)

Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl Ts tosyl (i.e. p-toluenesulfonyl) Cbz benzyloxycarbonyl Pbf pentamethyldihydrobenzofuran-5-sulfonyl

-   -   for the hydroxy group (as is present e.g. in the side-chain of         threonine and serine)

tBu tert.-butyl Bn benzyl Trt trityl

-   -   and for the mercapto group (as is present e.g. in the side-chain         of cysteine)

Acm acetamidomethyl tBu tert.-butyl Bn benzyl Trt trityl Mtr 4-methoxytrityl.

The 9-fluorenylmethoxycarbonyl-(Fmoc)-protected amino acid derivatives are preferably used as the building blocks for the construction of the template-fixed β-hairpin loop mimetics of formula I. For the deprotection, i.e. cleaving off of the Fmoc group, 20% piperidine in DMF or 2% DBU/2% piperidine in DMF can be used.

The quantity of the reactant, i.e. of the amino acid derivative, is usually 1 to 20 equivalents based on the milliequivalents per gram (meq/g) loading of the functionalized solid support (typically 0.1 to 2.85 meq/g for polystyrene resins) originally weighed into the reaction tube. Additional equivalents of reactants can be used, if required, to drive the reaction to completion in a reasonable time. The reaction tubes, in combination with the holder block and the manifold, are reinserted into the reservoir block and the apparatus is fastened together. Gas flow through the manifold is initiated to provide a controlled environment, for example, nitrogen, argon, air and the like. The gas flow may also be heated or chilled prior to flow through the manifold. Heating or cooling of the reaction wells is achieved by heating the reaction block or cooling externally with isopropanol/dry ice and the like to bring about the desired synthetic reactions. Agitation is achieved by shaking or magnetic stirring (within the reaction tube). The preferred workstations (without, however, being limited thereto) are Labsource's Combi-chem station and MultiSyn Tech's-Syro synthesizer.

Amide bond formation requires the activation of the α-carboxyl group for the acylation step. When this activation is being carried out by means of the commonly used carbodiimides such as dicyclohexylcarbodiimide (DCC, Sheehan & Hess, J. Am. Chem. Soc. 1955, 77, 1067-1068) or diisopropylcarbodiimide (DIC, Sarantakis et al Biochem. Biophys. Res. Commun. 1976, 73, 336-342), the resulting dicyclohexylurea and diisopropylurea is insoluble and, respectively, soluble in the solvents generally used. In a variation of the carbodiimide method 1-hydroxybenzotriazole (HOBt, König & Geiger, Chem. Ber 1970, 103, 788-798) is included as an additive to the coupling mixture. HOBt prevents dehydration, suppresses racemization of the activated amino acids and acts as a catalyst to improve the sluggish coupling reactions. Certain phosphonium reagents have been used as direct coupling reagents, such as benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP, Castro et al., Tetrahedron Lett. 1975, 14, 1219-1222; Synthesis, 1976, 751-752), or benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexaflurophoshate (Py-BOP, Coste et al., Tetrahedron Lett. 1990, 31, 205-208), or 2-(1H-benzotriazol-1-yl-)1,1,3,3-tetramethyluronium terafluoroborate (TBTU), or hexafluorophosphate (HBTU, Knorr et al., Tetrahedron Lett. 1989, 30, 1927-1930); these phosphonium reagents are also suitable for in situ formation of HOBt esters with the protected amino acid derivatives. More recently diphenoxyphosphoryl azide (DPPA) or O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TATU) or O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU)/7-aza-1-hydroxy benzotriazole (HOAt, Carpino et al., Tetrahedron Lett. 1994, 35, 2279-2281) have also been used as coupling reagents.

Due to the fact that near-quantitative coupling reactions are essential, it is desirable to have experimental evidence for completion of the reactions. The ninhydrin test (Kaiser et al., Anal. Biochemistry 1970, 34, 595), where a positive colorimetric response to an aliquot of resin-bound peptide indicates qualitatively the presence of the primary amine, can easily and quickly be performed after each coupling step. Fmoc chemistry allows the spectrophotometric detection of the Fmoc chromophore when it is released with the base (Meienhofer et al., Int. J. Peptide Protein Res. 1979, 13, 35-42).

The resin-bound intermediate within each reaction tube is washed free of excess of retained reagents, of solvents, and of by-products by repetitive exposure to pure solvent(s) by one of the two following methods:

1) The reaction wells are filled with solvent (preferably 5 ml), the reaction tubes, in combination with the holder block and manifold, are immersed and agitated for 5 to 300 minutes, preferably 15 minutes, and drained by gravity followed by gas pressure applied through the manifold inlet (while closing the outlet) to expel the solvent;

2) The manifold is removed from the holder block, aliquots of solvent (preferably 5 ml) are dispensed through the top of the reaction tubes and drained by gravity through a filter into a receiving vessel such as a test tube or vial.

Both of the above washing procedures are repeated up to about 50 times (preferably about 10 times), monitoring the efficiency of reagent, solvent, and by-product removal by methods such as TLC, GC, or inspection of the washings.

The above described procedure of reacting the resin-bound compound with reagents within the reaction wells followed by removal of excess reagents, by-products, and solvents is repeated with each successive transformation until the final resin-bound fully protected linear peptide has been obtained.

Before this fully protected linear peptide is detached from the solid support, it is possible, if desired, to selectively deprotect one or several protected functional group(s) present in the molecule and to appropriately substitute the reactive group(s) thus liberated. To this effect, the functional group(s) in question must initially be protected by a protecting group which can be selectively removed without affecting the remaining protecting groups present. Alloc (allyloxycarbonyl) is an example for such an amino protecting group which can be selectively removed, e.g. by means of Pd° and phenylsilane in CH₂Cl₂, without affecting the remaining protecting groups, such as Fmoc, present in the molecule. The reactive group thus liberated can then be treated with an agent suitable for introducing the desired substituent. Thus, for example, an amino group can be acylated by means of an acylating agent corresponding to the acyl substituent to be introduced. For the formation of pegylated amino acids such as IPegK, or SPegK, preferably a solution of 5 equivalents of HATU (N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide) in dry DMF and a solution of 10 equivalents of DIPEA (Diisopropyl ethylamine) in dry DMF and 5 equivalents of 2-[2-(2-methoxyethoxy)ethoxy] acetic acid (1Peg) and, respectively, 2-(2-methoxyethoxy)acetic acid (sPeg), is applied to the liberated amino group of the appropriate amino acid side chain for 3 h. The procedure is thereafter repeated for another 3 h with a fresh solution of reagents after filtering and washing the resin.

Before this fully protected linear peptide is detached from the solid support, it is also possible, if desired, to form an interstrand linkages between side-chains of appropriate amino acid residues at positions 2 and 10.

Interstrand linkages and their formation have been discussed above, in connection with the explanations made regarding groups of the type H which can, for example, be disulfide bridges formed by cysteine and homocysteine residues at opposite positions of the β-strand; or lactam bridges formed by glutamic and aspartic acid residues linking ornithine and, respectively, lysine residues, or by glutamic acid residues linking 2,4-diaminobutyric acid residues located at opposite β-strand positions by amide bond formation. The formation of such interstrand linkages can be effected by methods well known in the art.

For the formation of disulfide bridges preferably a solution of 10 equivalents of iodine solution is applied in DMF or in a mixture of CH₂Cl₂/MeOH for 1.5 h which is repeated for another 3 h with a fresh iodine solution after filtering of the iodine solution, or in a mixture of DMSO and acetic acid solution, buffered with 5% with NaHCO₃ to pH 5-6 for 4 h, or in water adjusted to pH 8 with ammonium hydroxide solution by stirring for 24 h, or in ammonium acetate buffer adjusted to pH 8 in the presence of air, or in a solution of NMP and tri-n-butylphosphine (preferably 50 eq.).

Detachment of the fully protected linear peptide from the solid support is achieved by immersion of the reaction tubes, in combination with the holder block and manifold, in reaction wells containing a solution of the cleavage reagent (preferably 3 to 5 ml). Gas flow, temperature control, agitation, and reaction monitoring are implemented as described above and as desired to effect the detachment reaction. The reaction tubes, in combination with the holder block and manifold, are disassembled from the reservoir block and raised above the solution level but below the upper lip of the reaction wells, and gas pressure is applied through the manifold inlet (while closing the outlet) to efficiently expel the final product solution into the reservoir wells. The resin remaining in the reaction tubes is then washed 2 to 5 times as above with 3 to 5 ml of an appropriate solvent to extract (wash out) as much of the detached product as possible. The product solutions thus obtained are combined, taking care to avoid cross-mixing. The individual solutions/extracts are then manipulated as needed to isolate the final compounds. Typical manipulations include, but are not limited to, evaporation, concentration, liquid/liquid extraction, acidification, basification, neutralization or additional reactions in solution.

The solutions containing fully protected linear peptide derivatives which have been cleaved off from the solid support and neutralized with a base, are evaporated. Cyclization is then effected in solution using solvents such as DCM, DMF, dioxane, THF and the like. Various coupling reagents which were mentioned earlier can be used for the cyclization. The duration of the cyclization is about 6-48 hours, preferably about 16 hours. The progress of the reaction is followed, e.g. by RP-HPLC (Reverse Phase High Performance Liquid Chromatography). Then the solvent is removed by evaporation, the fully protected cyclic peptide derivative is dissolved in a solvent which is not miscible with water, such as DCM, and the solution is extracted with water or a mixture of water-miscible solvents, in order to remove any excess of the coupling reagent.

Finally, the fully protected peptide derivative is treated with 95% TFA, 2.5% H₂O, 2.5% TIS or another combination of scavengers for effecting the cleavage of protecting groups. The cleavage reaction time is commonly 30 minutes to 12 hours, preferably about 2.5 hours. The volatiles are evaporated to dryness and the crude peptide is dissolved in 20% AcOH in water and extracted with isopropyl ether or other solvents which are suitable therefor. The aqueous layer is collected and evaporated to dryness, and the fully deprotected cyclic peptide derivative of formula I is obtained as end-product.

Alternatively the detachment, cyclization and complete deprotection of the fully protected peptide from the solid support can be achieved manually in glass vessels.

Depending on its purity, this peptide derivative can be used directly for biological assays, or it has to be further purified, for example by preparative HPLC.

As mentioned earlier, it is thereafter possible, if desired, to convert a fully deprotected product of formula I thus obtained into a pharmaceutically acceptable salt or to convert a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula I or into a different, pharmaceutically acceptable, salt. Any of these operations can be carried out by methods well known in the art.

The template starting materials of formula II used in the processes of the invention, pre-starting materials therefor, and the preparation of these starting and pre-starting materials are described in International Application PCT/EP02/01711 of the same applicants, published as WO 02/070547 A1.

The β-hairpin peptidomimetics of the invention can be used in a wide range of applications where inflammatory diseases or pulmonary diseases or infections or immunological diseases or cardiovascular diseases or neurodegenerative diseases are mediated or resulting from serine protease activity, or where cancer is mediated or resulting from serine protease activity. For the control or prevention of a given illness or disease amenable to treatment with protease inhibitors, the β-hairpin peptidomimetics may be administered per se or may be applied as an appropriate formulation together with carriers, diluents or excipients well known in the art.

When used to treat or prevent diseases such as pulmonary emphysema, rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, cystic fibrosis, multiple sclerosis, adult respiratory distress syndrome, pancreatitis, asthma, allergic rhinitis, inflammatory dermatoses, post angioplasty restenosis, cardiac hypertrophy, heart failure or cancer such as, but not limited to, breast cancer, or cancer related to angiogenesis or metastasis, the β-hairpin peptidomimetics can be administered singly, as mixtures of several β-hairpin peptidomimetics, in combination with other anti-inflammatory agents, or antimicrobial agents or anti-cancer agents and/or in combination with other pharmaceutically active agents. The β-hairpin peptidomimetics can be administered per se or as pharmaceutical compositions.

Pharmaceutical compositions comprising β-hairpin peptidomimetics of the invention may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxilliaries which facilitate processing of the active β-hairpin peptidomimetics into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen.

For topical administration the β-hairpin peptidomimetics of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.

Systemic formulations include those designed for administration by injection, e.g. subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.

For injections, the β-hairpin peptidomimetics of the invention may be formulated in adequate solutions, preferably in physiologically compatible buffers such as Hink's solution, Ringer's solution, or physiological saline buffer. The solutions may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the β-hairpin peptidomimetics of the invention may be in powder form for combination with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation as known in the art.

For oral administration, the β-hairpin peptidomimetics of the invention can be readily formulated by combining them with pharmaceutically acceptable carriers well known in the art. Such carriers enable the β-hairpin peptidomimetics of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion by a patient to be treated. For oral formulations such as, for example, powders, capsules and tablets, suitable excipients include fillers such as sugars, e.g. lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents; and binding agents. If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate. If desired, solid dosage forms may be sugar-coated or enteric-coated using standard techniques.

For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. In addition, flavoring agents, preservatives, coloring agents and the like may be added.

For buccal administration, the composition may take the form of tablets, lozenges, etc., formulated as usual.

For administration by inhalation, the β-hairpin peptidomimetics of the invention are conveniently delivered in form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluromethane, carbon dioxide or another suitable gas. In the case of a pressurized aerosol the dose unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the β-hairpin peptidomimetics of the invention and a suitable powder base such as lactose or starch.

The compounds may also be formulated in rectal or vaginal compositions such as suppositories together with appropriate suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the β-hairpin peptidomimetics of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. For the manufacture of such depot preparations the β-hairpin peptidomimetics of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble salts.

In addition, other pharmaceutical delivery systems may be employed such as liposomes and emulsions well known in the art. Certain organic solvents such as dimethylsulfoxide may also be employed. Additionally, the β-hairpin peptidomimetics of the invention may be delivered using a sustained-release system, such as semipermeable matrices of solid polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for protein stabilization may be employed.

As the β-hairpin pepdidomimetics of the invention may contain charged residues, they may be included in any of the above-described formulations as such or as pharmaceutically acceptable salts. Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic solvents than are the corresponding free forms.

The β-hairpin peptidomimetics of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended purpose. It is to be understood that the amount used will depend on a particular application.

For topical administration to treat or prevent diseases amenable to treatment with beta hairpin mimetics a therapeutically effective dose can be determined using, for example, the in vitro assays provided in the examples. The treatment may be applied while the disease is visible, or even when it is not visible. An ordinary skilled expert will be able to determine therapeutically effective amounts to treat topical diseases without undue experimentation.

For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating β-hairpin peptidomimetic concentration range that includes the IC₅₀ as determined in the cell culture. Such information can be used to more accurately determine useful doses in humans.

Initial dosages can also be determined from in vivo data, e.g. animal models, using techniques that are well known in the art. One having ordinary skill in the art could readily optimize administration to humans based on animal data.

Dosage amounts for applications as serine protease inhibitory agents may be adjusted individually to provide plasma levels of the β-hairpin peptidomimetics of the invention which are sufficient to maintain the therapeutic effect. Therapeutically effective serum levels may be achieved by administering multiple doses each day.

In cases of local administration or selective uptake, the effective local concentration of the β-hairpin peptidomimetics of the invention may not be related to plasma concentration. One having the ordinary skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.

The amount of β-hairpin peptidomimetics administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

Normally, a therapeutically effective dose of the β-hairpin peptidomimetics described herein will provide therapeutic benefit without causing substantial toxicity.

Toxicity of the β-hairpin peptidomimetics of the invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD₅₀ (the dose lethal to 50% of the population) or the LD₁₀₀ (the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in humans. The dosage of the β-hairpin peptidomimetics of the invention lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage may vary within the range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dose can be chosen by the individual physician in view of the patient's condition (see, e.g. Fingl et al. 1975, In: The Pharmacological Basis of Therapeutics, Ch. 1, p. 1).

The following Examples illustrate the invention in more detail but are not intended to limit its scope in any way. The following abbreviations are used in these Examples:

-   -   HBTU: 1-benzotriazol-1-yl-tetramethylurounium         hexafluorophosphate (Knorr et al. Tetrahedron Lett. 1989, 30,         1927-1930);     -   HOBt: 1-hydroxybenzotriazole;     -   DIEA: diisopropylethylamine;     -   HOAT: 7-aza-1-hydroxybenzotriazole;     -   HATU: O-(7-aza-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronoium         hexafluorophosphate (Carpino et al. Tetrahedron Lett. 1994, 35,

EXAMPLES

1. Peptide Synthesis

Coupling of the First Protected Amino Acid Residue to the Resin

0.5 g of 2-chlorotritylchloride resin (Barbs et al. Tetrahedron Lett. 1989, 30, 3943-3946) (0.83 mMol/g, 0.415 mmol) was filled into a dried flask. The resin was suspended in CH₂Cl₂ (2.5 ml) and allowed to swell at room temperature under constant stirring for 30 min. The resin was treated with 0.415 mMol (1 eq) of the first suitably protected amino acid residue (see below) and 284 μl (4 eq) of diisopropylethylamine (DIEA) in CH₂Cl₂ (2.5 ml), the mixture was shaken at 25° C. for 4 hours. The resin colour changed to purple and the solution remained yellowish. The resin was shaken (CH₂Cl₂/MeOH/DIEA: 17/2/1), 30 ml for 30 min; then washed in the following order with CH₂Cl₂ (1×), DMF (1×), CH₂Cl₂ (1×), MeOH (1×), CH₂Cl₂ (1×), MeOH (1×), CH₂Cl₂ (2×), Et₂O (2×) and dried under vacuum for 6 hours.

Loading was typically 0.6-0.7 mMol/g.

The following preloaded resins were prepared: Fmoc-Pro-2-chlorotritylresin, Fmoc-Asp (OtBu)-2-chlorotritylresin, Fmoc-Pro(5RPhe)-2-chlorotritylresin, Fmoc-Leu-2-chlorotritylresin, Fmoc-Glu(OtBu)-2-chlorotritylresin, Fmoc-Asp(OtBu)-2-chlorotritylresin, Fmoc-Phe-2-chlorotritylresin, Fmoc-Gln(Trt)-2-chlorotritylresin, Fmoc-Ser (OtBu)-2-chlorotritylresin, Fmoc-Val-2-chlorotritylresin, Fmoc-Thr(OtBu)-2-chlorotritylresin and Fmoc-Ile-2-chlorotritylresin.

Synthesis of the Fully Protected Peptide Fragment

The synthesis was carried out using a Syro-peptide synthesizer (Multisyntech) using 24 to 96 reaction vessels. In each vessel were placed 60 mg (weight of the resin before loading) of the above resin. The following reaction cycles were programmed and carried out:

Step Reagent Time 1 CH₂Cl₂, wash and swell (manual) 3 × 1 min. 2 DMF, wash and swell 1 × 5 min. 3 40% piperidine/DMF 1 × 5 min. 4 DMF, wash 5 × 2 min. 5 5 equiv. Fmoc amino acid/DMF +5 eq. HBTU +5 eq. HOBt +5 eq. DIEA 1 × 120 min. 6 DMF, wash 4 × 2 min. 7 CH₂Cl₂, wash (at the end of the synthesis) 3 × 2 min.

Steps 3 to 6 are repeated to add each amino-acid.

After the synthesis of the fully protected peptide fragment had been terminated, then subsequently either Procedure A or Procedure B, as described hereinbelow, was adopted, depending on whether not interstrand linkages (i.e. disulfide (3-strand linkages) were to be formed.

Procedure A: Cyclization and Work up of Backbone Cyclized Peptides

Cleavage of the Fully Protected Peptide Fragment

After completion of the synthesis, the resin was suspended in 1 ml (0.39 mMol) of 1% TFA in CH₂Cl₂ (v/v) for 3 minutes, filtered and the filtrate was neutralized with 1 ml (1.17 mMol, 3 eq.) of 20% DIEA in CH₂Cl₂ (v/v). This procedure was repeated twice to ensure completion of the cleavage. An aliquot (200 μL) of the filtrate was fully deprotected with 0.5 ml of the cleavage mixture containing 95% trifluoroacetic acid (TFA), 2.5% water and 2.5% triisopropylsilane (TIS) and analysed by reverse phase-LC MS to monitor the efficiency of the linear peptide synthesis.

Cyclization of the Linear Peptide

The fully protected linear peptide was dissolved in DMF (8 ml, conc. 10 mg/ml). Two eq. of HATU (0.72 mMol) in 1 ml of DMF and 4 eq. of DIEA (1.44 mMol) in 1 ml of DMF were added, and the mixture was stirred at room temperature for 16 h. The volatile was evaporated to dryness. The crude cyclized peptide was dissolved in 7 ml of CH₂Cl₂ and extracted with 10% acetonitrile in water (4.5 ml) three times. The CH₂Cl₂ layer was evaporated to dryness.

Deprotection and Purification of the Cyclic Peptide

The cyclic peptide obtained was dissolved in 3 ml of the cleavage mixture containing 95% trifluoroacetic acid (TFA), 2.5% water and 2.5% triisopropylsilane (TIS). The mixture was left to stand at 20° C. for 2.5 hours and then concentrated under vacuum. The crude peptide was dissolved in 20% AcOH in water (7 ml) and extracted with diisopropylether (4 ml) three times. The aqueous layer was collected and evaporated to dryness, and the residue was purified by preparative reverse phase LC-MS.

After lyophilisation the products were obtained as white powders and analysed by LC-MS. The analytical data comprising purity after preparative HPLC and ESI-MS are shown in Table 1.

Analytical Method:

Analytical HPLC retention times (RT, in minutes) were determined using an Jupiter Proteo 90A, 150×2.0 mm, (cod. 00F4396-B0-Phenomenex) with the following solvents A (H₂O+0.1% TFA) and B (CH₃CN+0.1% TFA) and the gradient: 0 min: 95% A, 5% B; 20 min: 40% A 60% B; 21-23 min: 0% A, 100% B; 23.1-30 min: 95% A, 5% B.

Procedure B: Cyclization and Work Up of Backbone Cyclized Peptides having Disulfide β-Strand Linkages

Formation of Disulfide β-Strand Linkage

After completion of the synthesis, the resin was swelled in 3 ml of dry DMF for 1 h. Then 10 eq. of iodine solution in DMF (6 ml) were added to the reactor, followed by stirring for 1.5 h. The resin was filtered and a fresh solution of iodine (10 eq.) in DMF (6 ml) was added, followed by stirring for another 3 h. The resin was filtered and washed with DMF (3×) and CH₂Cl₂ (3×).

Backbone Cyclization, Cleavage and Purification of the Peptide

After formation of the disulfide β-strand linkage, the resin was suspended in 1 ml (0.39 mMol) of 1% TFA in CH₂Cl₂ (v/v) for 3 minutes and filtered, and the filtrate was neutralized with 1 ml (1.17 mMol, 3 eq.) of 20% DIEA in CH₂Cl₂ (v/v). This procedure was repeated twice to ensure completion of the cleavage. The resin was washed with 2 ml of CH₂Cl₂. The CH₂Cl₂ layer was evaporated to dryness.

The fully protected linear peptide was solubilized in 8 ml of dry DMF. Then 2 eq. of HATU in dry DMF (1 ml) and 4 eq. of DIPEA in dry DMF (1 ml) were added to the peptide, followed by stirring for 16 h. The volatiles were evaporated to dryness. The crude cyclized peptide was dissolved in 7 ml of CH₂Cl₂ and extracted with 10% acetonitrile in water (4.5 ml) three times. The CH₂Cl₂ layer was evaporated to dryness. To deprotect the peptide fully, 3 ml of cleavage cocktail TFA:TIS:H₂O (95:2.5:2.5) were added, and the mixture was kept for 2.5 h. The volatile was evaporated to dryness and the crude peptide was dissolved in 20% AcOH in water (7 ml) and extracted with diisopropyl ether (4 ml) for three times. The aqueous layer was collected and evaporated to dryness, and the residue was purified by preparative reverse phase LC-MS.

After lyophilisation the products were obtained as white powders and analysed by ESI-MS analytical method as described above. The analytical data comprising purity after preparative HPLC and ESI-MS are shown in Table 1.

Examples 1-45, 52-63, 65-67, 70-71, 75-114, 129, 131-162 and 179-196 are shown in Table 1. The peptides were synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. The linear peptides were synthesized on solid support according to the procedure described above in the following sequence: Resin-Pro-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Ex. 1-6, 9-45, 52-63, 65-67, 70-71, 75-103 112-114, 129, 131, 133, 136-138, 140-141, 143-146, 148-153, 155, 157-162 and 179-196 were cleaved from the resin, subjected to the disulfide bridge formation, cyclized, deprotected and purified as indicated in procedure B. Ex. 82, 123, 149, 159, 161 and 178 were cleaved from the resin as indicated in procedure B. The disulfide bridges were formed using the following procedure:

The crude product was solubilized in an ammonium acetate buffer 0.1M (pH adjusted to 8) (concentration: 1 mg of crude product per ml). The mixture was stirred at room temperature in presence of air. The reaction was monitored by reverse phase LC-MS. After reaction completion, the solution was evaporated to dryness and the residue purified by preparative reverse phase LC-MS.

The cyclization of the backbone was performed as indicated in procedure A. The deprotection was performed using the following procedure:

To deprotect the peptide fully, 5 ml of cleavage cocktail TFA:H₂O:Phenol:Thioanisol: Ethanedithiol (82.5:5:5:5:2.5) were added, and the mixture was kept for 5 h at room temperature. The peptide was precipitated by addition of cold diethylether (10 ml). After centrifugation, the supernatant phase was removed. The precipitate was washed three times with 5 ml of diethylether and was purified by preparative reverse phase LC-MS.

After lyophilisation the products were obtained as white powders and analysed by ESI-MS analytical method as described above.

Ex. 7, 8, 104-111, 132, 134, 135, 139, 142, 147, 154 and 156 were cleaved from the resin, cyclized, deprotected and purified as indicated in procedure A.

HPLC-retention times (minutes) were determined using the analytical method as described above:

Ex. 1 (15.37), Ex. 2 (11.54), Ex. 3 (7.82), Ex. 4 (8.62), Ex. 5 (16.51), Ex. 6 (13.67), Ex. 7 (3.61), Ex. 8 (4.11), Ex. 9 (5.82), Ex. 10 (7.98), Ex. 11 (8.38), Ex. 12 (6.80), Ex. 13 (7.41), Ex. 14 (6.20), Ex. 15 (8.68), Ex. 16 (9.82); Ex. 17 (5.59), Ex. 20 (7.32), Ex. 21 (8.66), Ex. 22 (8.68), Ex. 23 (12.66), Ex. 24 (8.67), Ex. 25 (7.53), Ex. 26 (9.02), Ex. 27 (8.06), Ex. 28 (9.62), Ex. 29 (8.78), Ex. 30 (10.49), Ex. 31 (5.50), Ex. 32 (7.45), Ex. 33 (8.39), Ex. 34 (10.16), Ex. 35 (9.04), Ex. 36 (10.98), Ex. 37 (7.56), Ex. 38 (9.29), Ex. 39 (8.32), Ex. 40 (10.11), Ex. 41 (7.23), Ex. 42 (8.83), Ex. 43 (7.92), Ex. 44 (9.87), Ex. 45 (8.26), Ex. 52 (6.20), Ex. 53 (8.68), Ex 54 (9.82), Ex. 55 (5.59), Ex. 56 (6.06), Ex. 57 (6.47), Ex. 58 (7.32), Ex. 59 (8.68), Ex. 60 (10.66), Ex. 61 (8.54), Ex. 62 (9.83), Ex. 63 (16.54), Ex. 65 (15.71), Ex. 66 (17.50), Ex. 67 (15.87), Ex. 70 (12.87), Ex. 71 (13.48), Ex. 75 (14.22), Ex. 76 (4.47), Ex. 77 (5.15), Ex. 78 (10.93), Ex. 79 (10.70), Ex. 80 (12.09), Ex. 81 (11.63), Ex. 82 (5.71), Ex. 83 (5.45), Ex. 84 (11.14), Ex. 85 (10.90), Ex. 86 (13.78), Ex. 87 (13.98), Ex. 88 (14.35), Ex. 89 (15.21), Ex. 90 (14.72), Ex. 91 (11.97), Ex. 92 (11.77), Ex. 93 (15.25), Ex. 94 (14.61), Ex. 95 (20.46), Ex. 96 (15.08), Ex. 97 (20.78), Ex. 98 (18.28), Ex. 99 (14.62), Ex. 100 (13.90), Ex. 101 (13.76), Ex. 102 (20.53), Ex. 103 (14.14), Ex. 104 (11.60), Ex. 105 (11.90), Ex. 106 (11.63), Ex. 107 (11.78), Ex. 108 (13.03), Ex. 109 (15.22), Ex. 110 (12.40), Ex. 111 (12.10), Ex. 112 (5.49), Ex. 113 (5.67), Ex. 114 (5.55), Ex. 129 (17.22), Ex. 131 (11.97), Ex. 132 (13.56), Ex. 133 (14.57), Ex. 134 (14.72), Ex. 135 (17.53), Ex. 136 (18.28), Ex. 137 (14.72), Ex. 138 (14.35), Ex. 139 (15.40), Ex. 140 (11.14), Ex. 141 (5.71), Ex. 142 (13.97), Ex. 143 (13.94), Ex. 144 (15.08), Ex. 145 (20.87), Ex. 146 (17.91), Ex. 147 (17.11), Ex. 148 (7.83), Ex. 149 (16.22), Ex. 150 (20.09), Ex. 151 (20.72), Ex. 152 (21.38), Ex. 153 (17.97), Ex. 154 (16.58), Ex. 155 (19.46), Ex. 156 (15.66), Ex. 157 (22.04), Ex. 158 (15.65), Ex. 159 (17.89), Ex. 160 (18.72), Ex. 161 (19.91), Ex. 162 (17.79), Ex. 179 (4.25), Ex. 180 (11.43), Ex. 181 (12.30), Ex. 182 (12.83), Ex. 183 (10.51), Ex. 184 (12.12), Ex. 185 (10.14), Ex. 186 (10.09), Ex. 187 (10.14), Ex. 188 (10.65), Ex. 189 (10.73), Ex. 190 (10.10), Ex. 191 (10.17), Ex. 192 (10.19), Ex. 193 (11.02), Ex. 194 (9.92), Ex. 195 (10.74), Ex. 196 (9.94).

Example 46 is shown in Table 1. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Asp(OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 46 (8.94).

Example 47 is shown in Table 1. The peptide was synthesized starting with the amino acid Asp which was grafted to the resin. Starting resin was Fmoc-Asp(OtBu)-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Asp(OtBu)-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method as described above:

Ex. 47 (7.29).

Example 48 is shown in Table 1. The peptide was synthesized starting with the amino acid Pro(5RPhe) which was grafted to the resin. Starting resin was Fmoc-Pro(5RPhe)-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro(5RPhe)-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B. HPLC-retention time (minutes) was determined using the analytical described above:

Ex. 48 (10.07).

Example 49 is shown in Table 1. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Ala-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 49 (8.09);

Example 50 is shown in Table 1. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Ile-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical described above:

Ex. 50 (9.78).

Example 51 is shown in Table 1. The peptide was synthesized starting with the amino acid Leu which was grafted to the resin. Starting resin was Fmoc-Leu-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Leu-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 51 (8.94);

Example 64 is shown in Table 1. The peptide was synthesized starting with the amino acid Glu which was grafted to the resin. Starting resin was Fmoc-Glu(OtBut)-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Glu(OtBu)-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 64 (13.17).

Example 68 is shown in Table 1. The peptide was synthesized starting with the amino acid Asp which was grafted to the resin. Starting resin was Fmoc-Asp(OtBu)-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Asp(OtBu)-^(D)Ala-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 68 (12.44).

Example 69 is shown in Table 1. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin Pro-^(D)Asn(Trt)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 69 (12.97).

Example 72 is shown in Table 1. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Thr(OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 72 (13.34).

Example 73 is shown in Table 1. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Ile-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 73 (9.78).

Example 74 is shown in Table 1. The peptide was synthesized starting with the amino acid Leu which was grafted to the resin. Starting resin was Fmoc-Leu-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Leu-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 74 (8.94).

Example 115 is shown in Table 1. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Asp(OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 115 (4.82).

Example 116 is shown in Table 1. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Phe-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 116 (5.98).

Example 117 is shown in Table 1. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Arg(Trt)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 117 (4.48).

Example 118 is shown in Table 1. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Ser(OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 118 (4.73).

Example 119 is shown in Table 1. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Val-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 119 (5.47).

Example 120 is shown in Table 1. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Pip-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the gradient method 1 described above:

Ex. 120 (5.48).

Example 121 is shown in Table 1. The peptide was synthesized starting with the amino acid Asp which was grafted to the resin. Starting resin was Fmoc-Asp(OtBu)-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Asp(OtBu)-^(D)Pro-P11-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 121 (4.56).

Examples 122 and 167 are shown in Table 1. The peptides were synthesized starting with the amino acid Phe which was grafted to the resin. Starting resin was Fmoc-Phe-2-chlorotrityl resin, which was prepared as described above. The linear peptides were synthesized on solid support according to procedure described above in the following sequence: Resin-Phe-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 122 (5.75); 167 (5.75).

Examples 123, 164, 169, 170, 172, 173, 175, 177 and 178 are shown in Table 1. The peptides were synthesized starting with the amino acid Gln which was grafted to the resin. Starting resin was Fmoc-Gln(Trt)-2-chlorotrityl resin, which was prepared as described above. The linear peptides were synthesized on solid support according to procedure described above in the following sequence: Resin-Gln(Trt)-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 123 (4.35), 164 (13.20), 169 (16.81), 170 (14.57), 172 (16.78), 173 (13.57), 175 (15.94), 177 (16.78), 178 (17.45).

Example 124 is shown in Table 1. The peptide was synthesized starting with the amino acid Ser which was grafted to the resin. Starting resin was Fmoc-Ser(OtBu)-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Ser(OtBu)-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 124 (4.46).

Example 125 is shown in Table 1. The peptide was synthesized starting with the amino acid Val which was grafted to the resin. Starting resin was Fmoc-Val-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Val-^(D)Pro-P11-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 125 (18.42).

Example 126 is shown in Table 1. The peptide was synthesized starting with the amino acid Thr which was grafted to the resin. Starting resin was Fmoc-Thr(OtBu)-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Thr(OtBu)-^(D)Thr(OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 126 (4.35).

Examples 127, 163, 165 and 174 are shown in Table 1. The peptides were synthesized starting with the amino acid Glu which was grafted to the resin. Starting resin was Fmoc-Glu(OtBu)-2-chlorotrityl resin, which was prepared as described above. The linear peptides were synthesized on solid support according to procedure described above in the following sequence: Resin-Glu(OtBu)-^(D)Lys(Boc)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 127 (4.11), 163 (14.93), 165 (14.40), 174 (12.73).

Example 128 is shown in Table 1. The peptide is synthesized starting with the amino acid Thr which was grafted to the resin. Starting resin was Fmoc-Thr(OtBu)-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Thr(OtBu)-^(D)Phe-P11-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the gradient method 1 described above:

Ex. 128 (5.26).

Example 130 is shown in Table 1. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Ala-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 130 (14.79).

Example 166 is shown in Table 1. The peptide was synthesized starting with the amino acid Ile which was grafted to the resin. Starting resin was Fmoc-Ile-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Ile-^(D)Phe-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 166 (16.80).

Example 168 is shown in Table 1. The peptide was synthesized starting with the amino acid Asp which was grafted to the resin. Starting resin was Fmoc-Asp(OtBu)-2-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Asp(OtBu)-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical described above:

Ex. 168 (4.56).

Examples 171 and 176 are shown in Table 1. The peptides were synthesized starting with the amino acid Gln which was grafted to the resin. Starting resin was Fmoc-Gln(Trt)-2-chlorotrityl resin, which was prepared as described above. The linear peptides were synthesized on solid support according to procedure described above in the following sequence: Resin-Gln(TrO-^(D)Gln(Trt)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical method described above:

Ex. 171 (15.40), 176 (13.67).

TABLE 1 Examples Ex- ample Sequ.ID P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 Template Purity%^(a)) [M + H]   1 SEQ ID NO: 1 Phe Cys Thr Lys Ser Glu Pro Pro Ile Cys Thr ^(D)Pro^(L)Pro 95 1385.7   2 SEQ ID NO: 2 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Asp ^(D)Pro^(L)Pro 93 1399.5   3 SEQ ID NO: 3 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Asn ^(D)Pro^(L)Pro 95 1398.5   4 SEQ ID NO: 4 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Pro 95 1371.1   5 SEQ ID NO: 5 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro 95 1447.5   6 SEQ ID NO: 6 Tyr Cys Thr Lys Ser Asp Pro Pro Ile Cys Thr ^(D)Pro^(L)Pro 95 1401.7   7 SEQ ID NO: 7 Arg Glu Thr Lys Ser Asp Pro Pro Ile Arg Phe ^(D)Pro^(L)Pro 95 1521.2   8 SEQ ID NO: 8 Arg Nle Thr Lys Ser Asp Pro Pro Ile Nle Phe ^(D)Pro^(L)Pro 95 1462.4   9 SEQ ID NO: 9 4AmPhe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Pro 92 1386.9  10 SEQ ID NO: 10 Nle Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Pro 93 1337.8  11 SEQ ID NO: 11 Chg Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Pro 95 1363.8  12 SEQ ID NO: 12 Chg Cys Thr Lys Ser Asp Pro Pro Ile Cys Arg ^(D)Pro^(L)Pro 95 1432.7  13 SEQ ID NO: 13 2Cl-Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Arg ^(D)Pro^(L)Pro 95 1474.5  14 SEQ ID NO: 14 Ile Cys Thr Lys Ser Asp Pro Ala Ile Cys Arg ^(D)Pro^(L)Pro 93 1380.5  15 SEQ ID NO: 15 Phe Cys Thr Lys Ser Asp Pro Pro Nle Cys Ser ^(D)Pro^(L)Pro 95 1371.8  16 SEQ ID NO: 16 Phe Cys Thr Lys Ser Asp Pro Pro Cha Cys Ser ^(D)Pro^(L)Pro 95 1411.6  17 SEQ ID NO: 17 Ile Cys Thr Lys Ser Asp Pro Pro Gln Cys Arg ^(D)Pro^(L)Pro 95 1421.6  18 SEQ ID NO: 18 Ile Cys Thr Lys Ser Asp Pro Pro Tyr Cys Arg ^(D)Pro^(L)Pro 89 1456.6  19 SEQ ID NO: 19 Ile Cys Thr Lys Ser Asp Pro Pro Nle Cys Arg ^(D)Pro^(L)Pro 95 1476.6  20 SEQ ID NO: 20 Ile Cys Thr Lys Ser Asp Pro Pro Cha Cys Arg ^(D)Pro^(L)Pro 95 1446.5  21 SEQ ID NO: 21 Phe Cys Thr Lys Ser Glu Pro Pro Ile Cys Ser ^(D)Pro^(L)Pro 95 1385.8  22 SEQ ID NO: 22 Ile Cys Thr Nle Ser Asp Pro Pro Ile Cys Arg ^(D)Pro^(L)Pro 95 1391.6  23 SEQ ID NO: 23 Phe Cys Thr Nle Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro 95 1432.7  24 SEQ ID NO: 24 Phe Cys Thr Lys AlloThr Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Pro 95 1385.7  25 SEQ ID NO: 25 Phe Cys Thr Lys Dpr Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Pro 95 1370.9  26 SEQ ID NO: 26 Tyr Cys Thr Lys Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro 95 1463.8  27 SEQ ID NO: 27 hPhe Cys Thr Lys Ser Asp Pro Pro Ile Cys Asn ^(D)Pro^(L)Pro 95 1412.6  28 SEQ ID NO: 28 hPhe Cys Thr Lys Ser Asp Pro Pro Ile Cys Thr ^(D)Pro^(L)Pro 95 1399.7  29 SEQ ID NO: 29 hPhe Cys Thr Lys Ser Asp Pro Pro Ile Cys Asp ^(D)Pro^(L)Pro 95 1413.6  30 SEQ ID NO: 30 hPhe Cys Thr Lys Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro 95 1461.7  31 SEQ ID NO: 31 4AmPhe Cys Thr Lys Ser Asp Pro Pro Ile Cys Asn ^(D)Pro^(L)Pro 91 1413.8  32 SEQ ID NO: 32 4AmPhe Cys Thr Lys Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro 93 1462.7  33 SEQ ID NO: 33 Cha Cys Thr Lys Ser Asp Pro Pro Ile Cys Asn ^(D)Pro^(L)Pro 94 1404.8  34 SEQ ID NO: 34 Cha Cys Thr Lys Ser Asp Pro Pro Ile Cys Thr ^(D)Pro^(L)Pro 95 1391.7  35 SEQ ID NO: 35 Cha Cys Thr Lys Ser Asp Pro Pro Ile Cys Asp ^(D)Pro^(L)Pro 95 1405.8  36 SEQ ID NO: 36 Cha Cys Thr Lys Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro 95 1453.8  37 SEQ ID NO: 37 Chg Cys Thr Lys Ser Asp Pro Pro Ile Cys Asn ^(D)Pro^(L)Pro 95 1390.7  38 SEQ ID NO: 38 Chg Cys Thr Lys Ser Asp Pro Pro Ile Cys Thr ^(D)Pro^(L)Pro 95 1377.6  39 SEQ ID NO: 39 Chg Cys Thr Lys Ser Asp Pro Pro Ile Cys Asp ^(D)Pro^(L)Pro 95 1391.6  40 SEQ ID NO: 40 Chg Cys Thr Lys Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro 95 1439.6  41 SEQ ID NO: 41 Nle Cys Thr Lys Ser Asp Pro Pro Ile Cys Asn ^(D)Pro^(L)Pro 95 1364.7  42 SEQ ID NO: 42 Nle Cys Thr Lys Ser Asp Pro Pro Ile Cys Thr ^(D)Pro^(L)Pro 93 1351.7  43 SEQ ID NO: 43 Nle Cys Thr Lys Ser Asp Pro Pro Ile Cys Asp ^(D)Pro^(L)Pro 95 1365.7  44 SEQ ID NO: 44 Nle Cys Thr Lys Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro 95 1413.6  45 SEQ ID NO: 45 2Cl-Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Asn ^(D)Pro^(L)Pro 95 1432.6  46 SEQ ID NO: 46 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Asp^(L)Pro 95 1389.6  47 SEQ ID NO: 47 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Asp 95 1389.6  48 SEQ ID NO: 48 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Pro 95 1447.5   (5RPhe)  49 SEQ ID NO: 49 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Ala^(L)Pro 95 1345.6  50 SEQ ID NO: 50 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Ile^(L)Pro 94 1387.9  51 SEQ ID NO: 51 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Leu 94 1395.7  52 SEQ ID NO: 52 Ile Cys Thr Lys Ser Asp Pro Ala Ile Cys Arg ^(D)Pro^(L)Pro 93 1380.7  53 SEQ ID NO: 53 Phe Cys Thr Lys Ser Asp Pro Pro Nle Cys Ser ^(D)Pro^(L)Pro 95 1371.8  54 SEQ ID NO: 54 Phe Cys Thr Lys Ser Asp Pro Pro Cha Cys Ser ^(D)Pro^(L)Pro 95 1411.6  55 SEQ ID NO: 55 Ile Cys Thr Lys Ser Asp Pro Pro Gln Cys Arg ^(D)Pro^(L)Pro 95 1421.6  56 SEQ ID NO: 56 Ile Cys Thr Lys Ser Asp Pro Pro Tyr Cys Arg ^(D)Pro^(L)Pro 89 1456.5  57 SEQ ID NO: 57 Ile Cys Thr Lys Ser Asp Pro Pro Nle Cys Arg ^(D)Pro^(L)Pro 94 1406.6  58 SEQ ID NO: 58 Ile Cys Thr Lys Ser Asp Pro Pro Cha Cys Arg ^(D)Pro^(L)Pro 95 1446.5  59 SEQ ID NO: 59 Ile Cys Thr Nle Ser Asp Pro Pro Ile Cys Arg ^(D)Pro^(L)Pro 95 1391.6  60 SEQ ID NO: 60 Phe Cys Thr Nle Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro 95 1432.7  62 SEQ ID NO: 62 1-Nal Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Pro 95 1421.9  63 SEQ ID NO: 63 Chg Cys Thr Lys Ser Asp Pro Pro Nle Cys Tyr ^(D)Pro^(L)Pro 95 1439.  64 SEQ ID NO: 64 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Glu 95 1403.8  65 SEQ ID NO: 65 Chg Cys Thr Lys Ser Asp Pro Pro Tyr Cys Tyr ^(D)Pro^(L)Pro 95 1489.5  66 SEQ ID NO: 66 Chg Cys Thr Lys Ser Asp Pro Pro Cha Cys Tyr ^(D)Pro^(L)Pro 95 1479.6  67 SEQ ID NO: 67 Chg Cys Thr Lys AlloThr Asp Pro Pro Tyr Cys Tyr ^(D)Pro^(L)Pro 95 1503.6  68 SEQ ID NO: 68 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Ala^(L)Asp 95 1363.6  69 SEQ ID NO: 69 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Asn^(L)Pro 90 1388.8  70 SEQ ID NO: 70 4AmPhe Cys Thr Lys Ser Asp Pro Pro Cha Cys Asn ^(D)Pro^(L)Pro 92 1454.5  71 SEQ ID NO: 71 Chg Cys Thr Lys Ser Asp Pro Pro Cha Cys Arg ^(D)Pro^(L)Pro 95 1472.6  72 SEQ ID NO: 72 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Thr^(L)Pro 95 1375.6  73 SEQ ID NO: 73 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Ile^(L)Pro 94 1387.9  74 SEQ ID NO: 74 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Leu 94 1387.9  75 SEQ ID NO: 75 Arg Cys Thr Lys Ser Asp Pro Pro Ile Cys Phe ^(D)Pro^(L)Pro 95 1440.5  76 SEQ ID NO: 76 Ile Cys Thr Ala Ser Leu Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1369.3  77 SEQ ID NO: 77 Nle Cys Thr Thr Ser Ile Pro Pro Tyr Cys Tyr ^(D)Pro^(L)Pro 95 1434.3  78 SEQ ID NO: 78 Nle Cys Thr Abu Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1383.6  79 SEQ ID NO: 79 Nle Cys Thr Ala Ser Nle Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1369.8  80 SEQ ID NO: 80 Nle Cys Thr Ala Ser Aoc Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1397.6  81 SEQ ID NO: 81 Nle Cys Thr Ala Ser OctG Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1425.6  82 SEQ ID NO: 82 Nle Cys Thr Ala Ser Cha Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1409.5  83 SEQ ID NO: 83 Nle Cys Thr Ala Ser hLeu Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1383.6  84 SEQ ID NO: 84 Nle Cys Thr Ala Ser Chg Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1395.7  85 SEQ ID NO: 85 Nle Cys Thr Ala Ser t-BuAla Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1383.6  86 SEQ ID NO: 86 Nle Cys Ala Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1340.1  87 SEQ ID NO: 87 Nle Cys Abu Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1354.0  88 SEQ ID NO: 88 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1488.6   (4NHCOPhe)  89 SEQ ID NO: 89 Nle Cys Thr Ala Ser Ile Pro Pro Phe Cys Tyr ^(D)Pro^(L)Pro 88 1388.7  90 SEQ ID NO: 90 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Phe ^(D)Pro^(L)Pro 95 1353.6  91 SEQ ID NO: 91 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 95 1334.5  92 SEQ ID NO: 92 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Arg ^(D)Pro^(L)Pro 56 1362.6  93 SEQ ID NO: 93 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Ser ^(D)Pro^(L)Pro 95 1293.7  94 SEQ ID NO: 94 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Nle ^(D)Pro^(L)Pro 95 1319.5  95 SEQ ID NO: 95 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys 2- ^(D)Pro^(L)Pro 94 1404.0 Nal  96 SEQ ID NO: 96 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys 2Cl- ^(D)Pro^(L)Pro 94 1387.8 Phe  97 SEQ ID NO: 97 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Cha ^(D)Pro^(L)Pro 95 1359.8  98 SEQ ID NO: 98 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Phg ^(D)Pro^(L)Pro 95 1359.9  99 SEQ ID NO: 99 Aoc Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 93 1397.4 100 SEQ ID NO: 100 hLeu Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1383.4 101 SEQ ID NO: 101 Chg Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 87 1395.6 102 SEQ ID NO: 102 OctG Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1425.5 103 SEQ ID NO: 103 hPhe Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1417.5 104 SEQ ID NO: 104 Nle Glu Thr Ala Ser Ile Pro Pro Gln Lys Tyr ^(D)Pro^(L)Pro 95 1422.8 105 SEQ ID NO: 105 Nle Glu Thr Ala Ser Ile Pro Pro Gln Arg Tyr ^(D)Pro^(L)Pro 95 1450.9 106 SEQ ID NO: 106 Nle Thr Thr Ala Ser Ile Pro Pro Gln Lys Tyr ^(D)Pro^(L)Pro 95 1394.7 107 SEQ ID NO: 107 Nle Gln Thr Ala Ser Ile Pro Pro Gln Arg Tyr ^(D)Pro^(L)Pro 90 1449.8 108 SEQ ID NO: 108 Nle Thr Thr Ala Ser Ile Pro Pro Gln Met Tyr ^(D)Pro^(L)Pro 96 1397.7 109 SEQ ID NO: 109 Nle Gln Thr Ala Ser Ile Pro Pro Gln Thr Tyr ^(D)Pro^(L)Pro 95 1394.7 110 SEQ ID NO: 110 Nle Thr Thr Ala Ser Ile Pro Pro Gln Gln Tyr ^(D)Pro^(L)Pro 81 1394.6 111 SEQ ID NO: 111 Nle Gln Thr Ala Ser Ile Pro Pro Gln Ser Tyr ^(D)Pro^(L)Pro 95 1380.7 112 SEQ ID NO: 112 Nle Cys Thr Ala Ser C5a1 Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 85 1413.8 113 SEQ ID NO: 113 Nle Cys Thr Ala Ser Leu Pro Pro Tyr Cys Tyr ^(D)Pro^(L)Pro 95 1404.7 114 SEQ ID NO: 114 Ile Cys Thr Ala Ser Leu Pro Pro Tyr Cys Tyr ^(D)Pro^(L)Pro 95 1404.7 115 SEQ ID NO: 115 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Asp^(L)Pro 95 1387.8 116 SEQ ID NO: 116 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Phe^(L)Pro 95 1419.9 117 SEQ ID NO: 117 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Arg^(L)Pro 95 1428.6 118 SEQ ID NO: 118 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Ser^(L)Pro 95 1359.9 119 SEQ ID NO: 119 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Val^(L)Pro 95 1371.8 120 SEQ ID NO: 120 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pic^(L)Pro 95 1383.7 121 SEQ ID NO: 121 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Asp 95 1387.9 122 SEQ ID NO: 122 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Phe 95 1419.9 123 SEQ ID NO: 123 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Gln 95 1400.6 124 SEQ ID NO: 124 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Ser 95 1359.5 125 SEQ ID NO: 125 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Val 95 1371.8 126 SEQ ID NO: 126 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Thr^(L)Thr 95 1377.4 127 SEQ ID NO: 127 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Lys^(L)Glu 95 1433.5 128 SEQ ID NO: 128 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Phe^(L)Thr 95 1423.5 129 SEQ ID NO: 129 Nle Cys Thr Ala Ser OctG Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 91 1390.4 130 SEQ ID NO: 130 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Ala^(L)Pro 95 1343.5 131 SEQ ID NO: 131 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 95 1334.5 132 SEQ ID NO: 132 hPhe Glu Thr Ala Ser Ile Pro Pro Gln Lys Tyr ^(D)Pro^(L)Pro 95 1470.6 133 SEQ ID NO: 133 Nle Cys Thr Ala Ser Cha Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 95 1440.5 134 SEQ ID NO: 134 hPhe Thr Thr Ala Ser Ile Pro Pro Gln Gln Tyr ^(D)Pro^(L)Pro 95 1442.5 135 SEQ ID NO: 135 Nle Thr Thr Ala Ser OctG Pro Pro Gln Gln Tyr ^(D)Pro^(L)Pro 88 1450.7 136 SEQ ID NO: 136 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Phg ^(D)Pro^(L)Pro 95 1339.9 137 SEQ ID NO: 137 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Phe ^(D)Pro^(L)Pro 95 1353.6 138 SEQ ID NO: 138 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1488.6 (4NHCOPhe) 139 SEQ ID NO: 139 Nle Thr Thr Ala Ser Cha Pro Pro Gln Gln Tyr ^(D)Pro^(L)Pro 95 1434.8 140 SEQ ID NO: 140 Nle Cys Thr Ala Ser Chg Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1395.7 141 SEQ ID NO: 141 Nle Cys Thr Ala Ser Cha Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1409.5 142 SEQ ID NO: 142 hPhe Gln Thr Ala Ser Ile Pro Pro Gln Thr Tyr ^(D)Pro^(L)Pro 91 1406.5 143 SEQ ID NO: 143 hPhe Cys Thr Ala Ser Ile Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 94 1383.5 144 SEQ ID NO: 144 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys 2Cl- ^(D)Pro^(L)Pro 94 1387.8 Phe 145 SEQ ID NO: 145 OctG Cys Thr Ala Ser Ile Pro Pro Gln Cys Phe ^(D)Pro^(L)Pro 95 1409.4 146 SEQ ID NO: 146 hPhe Cys Thr Ala Ser Ile Pro Pro Gln Cys Phe ^(D)Pro^(L)Pro 95 1401.5 147 SEQ ID NO: 147 OctG Thr Thr Ala Ser Ile Pro Pro Gln Gln Tyr ^(D)Pro^(L)Pro 95 1450.9 148 SEQ ID NO: 148 OctG Cys Thr Ala Ser OctG Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 95 1446.6 149 SEQ ID NO: 149 OctG Cys Thr Ala Ser Ile Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 95 1390.4 150 SEQ ID NO: 150 OctG Cys Thr Ala Ser Cha Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1465.6 151 SEQ ID NO: 151 OctG Cys Thr Ala Ser OctG Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 94 1565.7 (4NHCOPhe) 152 SEQ ID NO: 152 hPhe Cys Thr Ala Ser OctG Pro Pro Gln Cys Phe ^(D)Pro^(L)Pro 95 1457.6 153 SEQ ID NO: 153 hPhe Cys Thr Ala Ser OctG Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 95 1438.5 154 SEQ ID NO: 154 OctG Gln Thr Ala Ser Ile Pro Pro Gln Thr Tyr ^(D)Pro^(L)Pro 93 1450.9 155 SEQ ID NO: 155 hPhe Cys Thr Ala Ser Cha Pro Pro Gln Cys Phe ^(D)Pro^(L)Pro 90 1441.5 156 SEQ ID NO: 156 OctG Glu Thr Ala Ser Ile Pro Pro Gln Lys Tyr ^(D)Pro^(L)Pro 95 1478.7 157 SEQ ID NO: 157 OctG Cys Thr Ala Ser Cha Pro Pro Gln Cys Phe ^(D)Pro^(L)Pro 95 1449.8 158 SEQ ID NO: 158 hPhe Cys Thr Ala Ser Cha Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 94 1422.7 159 SEQ ID NO: 159 OctG Cys Thr Ala Ser Cha Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 93 1430.0 160 SEQ ID NO: 160 OctG Cys Thr Ala Ser Cha Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 95 1549.6 (4NHCOPhe) 161 SEQ ID NO: 161 hPhe Cys Thr Ala Ser OctG Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1473.4 162 SEQ ID NO: 162 hPhe Cys Thr Ala Ser Cha Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1457.3 163 SEQ ID NO: 163 Nle Cys Thr Ala Ser OctG Pro Pro Gln Cys Tyr ^(D)Lys^(L)Glu 95 1374.4 164 SEQ ID NO: 164 Nle Cys Thr Ala Ser Cha Pro Pro Gln Cys Gln ^(D)Pro^(L)Gln 95 1405.5 165 SEQ ID NO: 165 OctG Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Lys^(L)Glu 95 1488.0 166 SEQ ID NO: 166 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Ile 95 1385.6 167 SEQ ID NO: 167 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Phe 95 1419.9 168 SEQ ID NO: 168 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Asp 95 1387.9 169 SEQ ID NO: 169 Nle Cys Thr Ala Ser OctG Pro Pro Gln Cys Tyr ^(D)Pro^(L)Gln 95 1456.5 170 SEQ ID NO: 170 Nle Cys Thr Ala Ser Cha Pro Pro Gln Cys Tyr ^(D)Pro^(L)Gln 95 1440.5 171 SEQ ID NO: 171 Nle Cys Thr Ala Ser Cha Pro Pro Gln Cys Cha ^(D)Gln^(L)Gln 95 1461.0 172 SEQ ID NO: 172 Nle Cys Thr Ala Ser Cha Pro Pro Gln Cys Cha ^(D)Pro^(L)Gln 95 1430.6 173 SEQ ID NO: 173 hPhe Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Gln 95 1448.6 174 SEQ ID NO: 174 hPhe Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Lys^(L)Glu 95 1480.0 175 SEQ ID NO: 175 Nle Cys Thr Ala Ser Cha Pro Pro Gln Cys 2Cl- ^(D)Pro^(L)Gln 95 1458.5 Phe 176 SEQ ID NO: 176 Nle Cys Thr Ala Ser Cha Pro Pro Gln Cys Gln ^(D)Gln^(L)Gln 95 1555.5 (4NHCOPhe) 177 SEQ ID NO: 177 OctG Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Gln 95 1430.6 178 SEQ ID NO: 178 OctG Cys Thr Ala Ser OctG Pro Pro Gln Cys Gln ^(D)Pro^(L)Gln 95 1477.6 179 SEQ ID NO: 179 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 90 1369.7 180 SEQ ID NO: 180 Ile Cys Thr Lys Ser Leu Pro Pro Ile Cys Arg ^(D)Pro^(L)Pro 94 1404.8 181 SEQ ID NO: 181 Ile Cys Thr Lys Ser hPhe Pro Pro Ile Cys Arg ^(D)Pro^(L)Pro 92 1452.6 182 SEQ ID NO: 182 Ile Cys Thr Lys Ser Cha Pro Pro Ile Cys Arg ^(D)Pro^(L)Pro 95 1444.6 183 SEQ ID NO: 183 Ile Cys Thr Lys Ser Tyr Pro Pro Ile Cys Arg ^(D)Pro^(L)Pro 91 1454.5 184 SEQ ID NO: 184 Phe Cys Thr Lys Ser Leu Pro Pro Ile Cys Arg ^(D)Pro^(L)Pro 95 1438.6 185 SEQ ID NO: 185 Ile Cys Thr Lys Ser Leu Pro Pro Arg Cys Arg ^(D)Pro^(L)Pro 95 1447.5 186 SEQ ID NO: 186 Ile Cys Thr Lys Ser Leu Pro Pro Lys Cys Arg ^(D)Pro^(L)Pro 95 1419.9 187 SEQ ID NO: 187 Ile Cys Thr Lys Ser Leu Pro Pro His Cys Arg ^(D)Pro^(L)Pro 95 1428.6 188 SEQ ID NO: 188 Ile Cys Thr Lys Ser Leu Pro Pro Gln Cys Arg ^(D)Pro^(L)Pro 95 1419.8 189 SEQ ID NO: 189 Ile Cys Thr Lys Ser Leu Pro Pro Thr Cys Arg ^(D)Pro^(L)Pro 95 1392.4 190 SEQ ID NO: 190 Ile Cys Thr Lys Ser Leu Pro Pro Arg Cys Lys ^(D)Pro^(L)Pro 95 1420.1 191 SEQ ID NO: 191 Leu Cys Thr Lys Ser Leu Pro Pro Lys Cys Arg ^(D)Pro^(L)Pro 95 1420.0 192 SEQ ID NO: 192 Nle Cys Thr Lys Ser Leu Pro Pro Lys Cys Arg ^(D)Pro^(L)Pro 95 1420.0 193 SEQ ID NO: 193 Cha Cys Thr Lys Ser Leu Pro Pro Lys Cys Arg ^(D)Pro^(L)Pro 95 1459.7 194 SEQ ID NO: 194 Tyr Cys Thr Lys Ser Leu Pro Pro Lys Cys Arg ^(D)Pro^(L)Pro 95 1469.6 195 SEQ ID NO: 195 Trp Cys Thr Lys Ser Leu Pro Pro Lys Cys Arg ^(D)Pro^(L)Pro 92 1492.6 196 SEQ ID NO: 196 Arg Cys Thr Lys Ser Leu Pro Pro Lys Cys Tyr ^(D)Pro^(L)Pro 95 1469.6 ^(a))%-purity of compounds after prep. HPLC Cys in pos. 2 and 10 in Ex. 1-6, 9-103, 112-131, 133, 136-138, 140-141, 143-146, 148-153, 155, 157-196 form a disulfide bridge 2. Biological Methods 2.1. Preparation of the Peptide Samples.

Lyophilized peptides were weighed on a Microbalance (Mettler MT5) and dissolved in sterile water to a final concentration of 1 mM unless stated otherwise. Stock solutions were kept at +4° C., light protected.

2.2. Enzymatic Assays

Enzyme and substrate conditions were as indicated Table 2.

Kinetic measurements were made in a total reaction volume of 100 μl in 96 well flat bottomed plates (Greiner) on a Genios plate reader (Tecan). The enzyme was combined with the peptides (inhibitors) in a buffer containing 100 mM HEPES (pH 7.5), 50 mM CaCl₂, 0.025% Tween-20, 5% DMSO, and 1 mM of the substrate. The rate of substrate hydrolysis was measured by monitoring the change in absorbance at 405 nm over 30 minutes to verify linearity of the reaction curve. The average rate from minute 1 through minute 10 was used for all calculations. Initial calculations of background subtraction, average rate, duplicate averaging and % inhibition were made using the Magellan software (version 5) from Tecan. IC50% calculations were made using Grafit (version 5.0.10) from Erithacus Software by fitting inhibition data from 6 different inhibitor concentrations to a 4-parameter equation:

$y = \frac{100\%}{1 + \left( \frac{x}{{IC}_{50}} \right)^{s}}$

In this equation s is the slope factor, x is the inhibitor concentration and y is % inhibition at a given concentration of the inhibitor.

K_(m)/K_(i) Determination

The K_(m) for the serine protease substrate was determined from a Lineweaver-Burke plot (Grafit v5). The values for inhibitors were calculated using the formula K_(i)=IC50%/(1+([substrate]/K_(m))).

Increasing concentrations of substrate were reacted with the enzyme and the rate of each reaction (ABS/mSec) was plotted vs. substrate concentration. The reciprocal plot (Lineweaver-Burke) was also plotted to give K_(m) and V_(max) (inset) (see ref. 1 below).

TABLE 2 Substrate Enzyme concentration concentration Enzyme/Supplier in assay Substrate/Supplier in assay (mM) Elastase from human 0.6 mU/reaction N-Met-Ala-Pro-Val-p- 1 neutrophils/Serva nitroanilide/Sigma CathepsinG, from human 1 mU/reaction N-Succinyl-Ala-Pro- 1 neutrophils Phe-p-nitroanilide CAS nr. 107200-92-0 Sigma Calbiochem Trypsin, Iodination grade, 1 mU/reaction N-Benzoyl-Arg-p- 0.32 from human pancreas, nitroanilide CAS nr. 9002-07-7 Sigma Calbiochem Chymase, from 9 mU/reaction N-Succinyl-Ala-Pro- 1.5 human skin Phe-p-nitroanilide Calbiochem Sigma Thrombin, from Human 100 mU/reaction Benzoyl-Phe-Val-Arg- 0.5 Plasma, high activity, p-nitroanilide CAS nr. 9002-04-4 Calbiochem Calbiochem Chymotrypsin, from 1.6 microM/reaction N-Succinyl-Ala-Pro- 1 human pancreas Phe-p-nitroanilide CAS nr 9004-07-3 Sigma Calbiochem Coagulation Factor Xa, 0.4 mU/reaction Methoxycarbonyl-D- 2 from uman plasma, Nle-Gly-Arg-p- CAS nr. 9002-05-5 nitroanilid Calbiochem Roche Tryptase, from human 12.5 mU/reaction N-Benzoyl-Arg-p- 1.28 lung nitroanilide Calbiochem Sigma Urokinase from human 250 mU/reaction Pyroglu-Gly-Arg-p- 0.5 urine/Sigma Aldrich nitroanilide x HCl CAS nr. 9039-53-6 Endotell Kallikrein, from human 0.34 microgram/reaction N-Benzoyl-Pro-Phe- 1 plasma, Arg-p-nitroanilide CAS Nr 9001-01-8 Sigma Calbiochem Plasmin from human 2 mU/reaction D-Val-Leu-Lys-p- 5 plasma, Nitroanilide CAS nr. 9001-90-5 Sigma Sigma-Aldrich 2.3. Cytotoxicity Assay

The cytotoxicity of the peptides to HELA cells (Acc57) and COS-7 cells (CRL-1651) was determined using the MTT reduction assay [see ref. 2 and 3, below]. Briefly the method was as follows: HELA cells and COS-7 cells were seeded at 7.0×10³ and, respectively, 4.5×10³ cells per well and grown in 96-well microtiter plates for 24 hours at 37° C. at 5% CO₂. At this point, time zero (Tz) was determined by MTT reduction (see below). The supernatant of the remaining wells was discarded, and fresh medium and the peptides in serial dilutions of 12.5, 25 and 50 μM were pipetted into the wells. Each peptide concentration was assayed in triplicate. Incubation of the cells was continued for 48 hours at 37° C. at 5% CO₂. Wells were then washed once with phosphate buffered saline (PBS) and subsequently 100 μl MTT reagent (0.5 mg/ml in medium RPMI1640 and, respectively, DMEM) were added to the wells. This was incubated at 37° C. for 2 hours and subsequently the medium was aspirated and 100 μl isopropanol were added to each well. The absorbance at 595 nm of the solubilized product was measured (OD595peptide). For each concentration averages were calculated from triplicates. The percentage of growth was calculated as follows: (OD595peptide-OD595Tz-OD595Empty well)/(OD595Tz-OD₅₉₅Empty well)×100% and was plotted for each peptide concentration. The LC 50 values (Lethal Concentration, defined as the concentration that kills 50% of the cells) were determined for each peptide by using the trend line function of EXCEL (Microsoft Office 2000) for the concentrations (50, 25, 12.5 and 0 μM), the corresponding growth percentages and the value −50, (=TREND(C50:CO₃%50:%0, −50)).

The GI 50 (Growth Inhibition) concentrations were calculated for each peptide by using a trend line function for the concentrations (50, 25, 12.5 and 0 μg/ml), the corresponding percentages and the value 50, (=TREND (C₅₀:C₀, %₅₀:%₀,50).

2.4. Hemolysis

The peptides were tested for their hemolytic activity against human red blood cells (hRBC). Fresh hRBC were washed three times with phosphate buffered saline (PBS) by centrifugation for 10 min at 2000×g. Peptides at a concentration of 100 μM were incubated with 20% v/v hRBC for 1 hour at 37° C. The final erythrocyte concentration was approximately 0.9×10⁹ cells per ml. A value of 0% and, respectively, 100% cell lysis was determined by incubation of the hRBC in the presence of PBS alone and, respectively, 0.1% Triton X-100 in H₂O. The samples were centrifuged, the supernatant was 20-fold diluted in PBS buffer and the optical density (OD) of the sample at 540 nM was measured. The 100% lysis value (OD₅₄₀H₂O) gave an OD₅₄₀ of approximately 1.3-1.8. Percent hemolysis was calculated as follows: (OD₅₄₀peptide/OD₅₄₀H₂O)×100%.

2.5 Plasma Stability

405 μl of plasma/albumin solution were placed in a polypropylene (PP) tube and spiked with 45 μl of compound from a 100 mM solution B, derived from 135 μl of PBS and 15 μl of 1 mM peptide in PBS, pH 7.4. 150 μl aliquots were transferred into individual wells of the 10 kDa filter plate (Millipore MAPPB 1010 Biomax membrane). For “0 minutes controls”: 270 μl of PBS were placed in a PP tube and 30 μl of stock solution B was added and vortexed. 150 μl of control solution were placed into one well of the filter plate and served as “filtered control”.

Further 150 μl of control solution were placed directly into a receiver well (reserved for filtrate) and served as “not-filtered control”. The entire plate including evaporation lid was incubated for 60 mM at 37° C. Plasma samples (rat plasma: Harlan Sera lab UK, human plasma: Blutspendezentrum Zürich) were centrifuged at least for 2 h at 4300 rpm (3500 g) and 15° C. in order to yield 100 μl filtrate. For “serum albumin”-samples (freshly prepared human albumin: Sigma A-4327, rat albumin: Sigma A-6272, all at 40 mg/ml concentration in PBS) approximately 1 hour of centrifugation was sufficient. The filtrates in the receiver PP plate were analysed by LC/MS as follows: Column: Jupiter C18 (Phenomenex), mobile phases: (A) 0.1% formic acid in water and (B) acetonitrile, gradient: 5%-100% (B) in 2 minutes, electrospray ionization, MRM detection (triple quadrupole). The peak areas were determined and triplicate values were averaged. The binding was expressed in percent of the (filtered and not-filtered time point 0 min) control 1 and 2 by: 100−(100×T₆₀/T₀). The average from these values was then calculated.

2.6. Pharmacokinetic study (PK)

Pharmacokinetic Study After Single Oral (Gavage) and Intravenous Administration in Rats

Pharmacokinetic study after single intravenous (i.v.) and oral (p.o., gavage) administration was performed for the compound of Example 75 (“Ex. 75”). 332 g (±10 g) male Wistar mice obtained from RCC Ltd, Laboratory animal Services, CH-4414 Füllinsdorf, Switzerland were used in the study. The vehicle, physiological saline, was added to give a final concentration of 2.5 mg/ml of the compound. The volume was 2 ml/kg i.v. and 10 ml/kg p.o. and the peptide Ex. 75 was injected to give a final intravenous dose of 5 mg/kg and an oral dose of 50 mg/kg. Blood samples (approx. 0.24 ml) were taken following the schedule below at different time points into heparinized tubes by automated blood sampling using the DiLab AccuSampler. When a problem occurred during automated blood sampling, blood was sampled by retro-orbital bleeding under light isoflurane anesthesia. Samples were taken at the following time points: 0, 5 min (only i.v.), 15, 30 min and 1, 2, 4, 8, 16, 24 and 36 (only p.o.) hours and added to heparinized tubes. Plasma was removed from pelleted cells upon centrifugation and frozen at 31 80° C. prior to HPLC-MS analysis.

Preparation of the Plasma Calibration Samples

“Blank” rat plasma from untreated animals was used. Aliquots of plasma of 0.1 ml each were spiked with 50 ng of propranolol (Internal Standard, IS), (sample preparation by solid phase extraction on OASIS® HLB cartridges (Waters)) and with known amounts of Ex. 75 in order to obtain 9 μl asma calibration samples in the range 5-2000 ng/ml. The OASIS® HLB cartridges were conditioned with 1 ml of methanol and then with 1 ml of 1% NH₃ in water. Samples were then diluted with 400 μl of 1% NH₃ in water and loaded. The plate was washed with 1 ml of methanol/1% NH₃ in water 5/95. Elution was performed using 1 ml of 0.1% TFA in methanol.

The plate containing eluates was introduced into the concentrator system and taken to dryness. The residues were dissolved in 100 μl of formic acid 0.1%/acetonitrile, 95/5 (v/v) and analysed in the HPLC/MS on a reverse phase analytical column (Jupiter C18, 50×2.0 mm, 5 μm, Phenomenex), using gradient elution (mobile phases A: 0.1% formic acid in water, B: Acetonitrile; from 5% B to 100% B in 2 min.).

Preparation of Plasma Samples

From each sample 100 μl of plasma were taken for the extraction. If the volume was less than 100 μl the appropriate amount of “blank” mouse plasma was added in order to keep the matrix identical to the calibration curve. Samples were then spiked with IS and processed as described for the calibration curve.

Pharmacokinetic Evaluation

PK analysis was performed on pooled data (generally n=2 or 3) using the software PK solutions 2.0™ (Summit Research Service, Montrose, Colo. 81401 USA). The area under the curve AUC was calculated by the linear trapezoidal rule. AUC_((t-∞)) was estimated as Ct/b (b: elimination rate constant). AUC_((t-∞)) is the sum of AUC_((0-t)) and AUC_((t-∞)). Elimination half-life was calculated by the linear regression on at least three data points during the elimination phase. The time intervals selected for the half-life determinations were evaluated by the correlation coefficient (r²), which should be at least above 0.85 and most optimally above 0.96. In case of i.v. administration the initial concentration at t_(zero) was determined by extrapolation of the curve through the first two time points. Finally bioavailability after i.p. administration was calculated from the normalised AUC_((0-∞)) ratio after i.p. versus i.v. administration.

3.0 Results

The results of the experiments described under 2.2-2.5, above, are indicated in Table 3 herein below.

TABLE 3 Uro- Hemo- Cathepsin Trypsin Chymo- Chymase Thrombin FXa kinase Tryptase Cyto- lysis at G Elastase at trypsin at at at at At toxicity 100 IC50 IC50 100 μM at 100 μM 100 μM 100 μM 100 μM 100 μM 100 μM LC₅₀/GI₅₀ μM Ex (nmol) (nmol) % % % % % % % Hela cells % 1 86 >100000     92.6   7.8 0   1.1 5.7 5.7 0  nd 0 2 84 >100000   92   2.9 0   9.2 5.3 0.9 39.6 nd nd 3 51 >100000   92 0 1   0   4   4   68   100  0 4 91 >100000   96   1.8 0   0   2.4 5.4 0  100  0 5 56 >100000   92 3 0   0.5 0.2 5.7 74   nd 0 6 ? nd nd nd nd nd nd nd nd nd nd 7 91 1.5 at 100 41 12  13.4  0   11.7  1.1  1.5 100    0.2 μM % 8 126  0.8 at 100   74.2   5.6 71.7  nd nd nd nd nd nd μM % 9 105  4.1 at 100   88.1 nd nd nd nd nd nd nd nd μM % 10 75 0.3 at 100   89.9 nd 9.4 nd nd nd nd nd nd μM % 11 95  19 at 100   6.5  73.6 12.1  nd nd nd nd nd nd μM % 12 90  37038 97 28  12   11   5   12   59.3   59.3 nd 13 100  8.2 at 100   95.0 nd 19.9  nd nd nd nd nd nd μM % 14 52 >100000   88 0 42.3  8.7 6   5.4 84.2 100  0 15   56.0 >100000     95.0  54.2 12.7  nd nd nd nd 100  0 16 66 >100000     90.0  17.9 12.9  nd nd 3.2 nd 94   0.1 17 55 >100000     90.0 16  27.6  0   nd nd 90.4 94   0.1 18 47 >100000   84 25  32.5  0   nd nd 88.3 100  0 19 41 >100000     94.0 0 26.9  11   32   4   85.2 100  0 20 48 >100000     97.0 0 44.1  28   25   6.7 nd 100  0 21 97     16.4   95.6   2.6 5   nd nd nd nd nd nd 22 55 >100000    84. 0 98.8  nd nd 5.7  3.8  8 0 23 38 >100000   90 4 60   0   11   9   29   51 0 24 71 >100000   97   1.0 1.2 3.5 30   5.1 0  99 nd 25 102  3.2 at   89.3 nd 10.0  nd nd nd nd nd nd 100 μM % 26 49 >100000 84   2.2 0   3   6   3.1 66.4 nd nd 27 48 nd nd nd nd nd nd nd nd nd nd 28 39 >100000 95 32  0   12   6   1   0  nd nd 29 42 nd nd nd nd nd nd nd nd nd nd 30 39  49900 98 49  0   2   3   9   nd nd nd 31 34 >100000   98 15  12   10   8   15   76   nd nd 32 52 nd nd nd nd nd nd nd nd nd nd 33 45 nd nd nd nd nd nd nd nd nd nd 34 56 nd nd nd nd nd nd nd nd nd nd 35 54 nd nd nd nd nd nd nd nd nd nd 36 41 nd Nd nd nd nd nd 0   73.3 83 0 37 35 nd nd nd nd nd nd 5   56   92   0.1 38 31 >100000   96 4 1   0   0   1   11   100  0 39 38 >100000   94 7 0   2   0   2   34   98 0 40 25  >44862   94 19  8   1   3   10   33   97   0.1 41 49 nd nd nd nd nd nd nd nd nd nd 42 46 nd nd nd nd nd nd 7   0  87 0 43 77 nd nd nd nd nd nd nd nd nd nd 44 31  >10000   100  24  3   9   9   14   50   67   0.1 45 47 nd nd nd nd nd nd nd nd nd nd 46   87.5 >100000   95 0 10.2  6.9 12.2  5.8 44.1 nd nd 47 64  >10000   87 1 8.2 0   9.3 6.3 0  100  0 48 83 >100000   93 3 nd nd nd nd nd nd nd 49 82  >10000   96 0 0   7.9 nd 6.2 30.5 nd nd 50 89 >100000   94 0 nd nd nd nd nd nd nd 51 91 >100000   nd nd nd nd nd nd nd nd nd 52 52 >100000   86 0 42.3  8.7 6   5.4 84.2 100  0 53 56 >100000   95 54  12.7  nd nd nd nd 63 0 54 66 >100000   90 18  12.9  nd nd 3.2 nd nd nd 55 55 >100000   90 16  27.6  nd nd nd 90.4 94   0.1 56 47 >100000   84 25  32.5  0   nd nd 88.3 100  0 57 41 >100000   94 0 26.9  11   32   4   82.2  0 0 58   47.5 >100000   97 0 44.1  28   25   6.7 nd 100  0 59 55 >100000   84 0 98.8  nd nd 5.7  3.8  8 0 60 38 >100000   90 4 60   0   11   9   29.4 51 0 61 72 nd nd nd nd nd nd nd nd nd nd 62 69 nd nd nd nd nd nd nd nd nd nd 63 41 >100000   96 11  7   1   0   0   50   87 0 64 45 >100000   87 0 0   2.3 0   3   0  59 0 65 47 nd nd nd nd nd nd 1   57   84 0 66 48 nd nd nd nd nd nd nd nd nd nd 67 48 nd nd nd nd nd nd nd nd nd nd 68 59 >100000     84.2   4.3 0   5.4 8.6 4.6 21.3 nd nd 69 68 nd nd nd nd nd nd nd nd nd nd 70 69 nd nd nd nd nd nd nd nd nd nd 71 70 nd nd nd nd nd nd nd nd nd nd 72 87 nd nd nd nd nd nd nd nd nd nd 73 89 >100000   94 0 nd nd nd nd nd nd Nd 74 91 >100000   86 >100000      nd nd nd nd nd nd nd 75 86 69.1 at 100    92.6 7.8 at 100 0   1.1 5.7 5.7 0  nd nd μM % μM % 76 nd   71 nd nd nd nd nd nd nd nd nd 77 nd   68 nd nd nd nd nd nd nd nd nd 78 nd   29 nd <4000     nd nd nd nd nd 61 nd 79 nd   66 nd nd nd nd nd nd nd nd nd 80 nd   35 nd >20000     nd nd nd nd nd 12 nd 81 61.3 at 100   28 100000   100000    nd 13.1  8.7 nd nd 58 nd μM % 82 nd   18 nd  72.9 nd nd 15.3  nd 44.5 nd nd 83 nd   43 nd 100000    nd nd nd nd nd 12 nd 84 20195     18   10.8 17103   0   20.6  13.3  10.4   4.2  9 nd 85 nd   28  0 >20000     nd 12.6  25.6  nd nd nd nd 86 47 at 100 μM   26  0 >100000      0   10.7  24.8  nd 0  nd nd % 87 nd   37 nd 106977    nd nd nd nd nd 65 nd 88 >100000       18   6.4 4309   0   0.2 3   96    0.6 73 nd 89 nd   43 nd nd nd nd nd nd nd 51 nd 90 66975     21   5.2 33074   0   0   5.5 3.5 5  96 nd 91 45 at 100 μM   28  0 48108   4.7 13.5  19.4  nd nd 79 nd % 92 nd   43 nd nd nd nd nd nd nd 93 nd 93 nd   41 nd nd nd nd nd nd  5.6 100  nd 94 nd   50 nd nd nd nd nd nd nd nd nd 95 38677     24   8.9 33729   0   0   11.3  10.3  0  89 nd 96 21175     15   7.5 15433   0   3.6 0   6.2 0  52 nd 97 >100000       24   9.5 77431   0   11.6  4.8 11.9  0  100  nd 98 >100000       21 0 38820   0   5.2 0   0   0  78 nd 99 85196     16   30.5 8558   0   0   0   17.4  0  58 nd 100 nd   35 nd nd nd nd nd nd nd 83 nd 101 nd   49 nd nd nd nd nd nd nd nd nd 102 >100000       13  0 4975   0   1.7 0   0.5 0  55 nd 103 >100000       18  6.4 4309   0   10.2  3   9.6  0.6 47 nd 104 53.5 at 100   34  0 3.1 at 100 μM 0   7.7 6.2 0   0  nd nd μM % % 105 nd   34 nd nd nd nd nd nd nd nd nd 106 nd   49 nd nd nd nd nd nd nd nd nd 107 nd   51 nd nd nd nd nd nd nd nd nd 108 nd   31 nd nd nd nd nd nd nd nd nd 109 54.1 at 100   33  0  13.8 0.1 0   5.6 nd nd nd nd μM % 110 nd   38 nd nd nd nd nd nd nd nd nd 111 nd   46 nd nd nd nd nd nd nd nd nd 112 nd   39 nd nd nd nd nd nd nd 33 nd 113 nd   35 nd nd nd nd nd nd nd nd nd 114 nd   47 nd nd nd nd nd nd nd 34 nd 115 nd   38 nd 27751   nd nd nd nd nd 51 nd 116 nd   46  0 39710   nd nd nd nd nd nd nd 117 nd   33 nd nd nd nd nd nd nd 29 nd 118 nd   43 nd nd nd nd nd nd nd nd nd 119 nd   45 nd nd nd nd nd nd nd nd nd 120 nd   29 nd nd nd nd nd nd nd 38 nd 121 11155     18   12.8   27526, IC50 1.2 0   5.6 5.7  4.6 49 nd (nmol) 122 35134     18 19   58000, IC50 6.4 0   19.6  11.1   0.2 29 nd (nmol) 123 35203     14   7.9   14995, IC50 0   2.7 0   7.6 nd nd nd (nmol) 124 nd   40 nd nd nd nd nd nd nd 40 nd 125 18269     15   28.3 >20000, IC50 4.8 0   0   nd nd 37 nd (nmol) 126 nd   36 nd nd nd nd nd nd nd nd nd 127 64 at 100 μM   29  0  47.2 1.9 3.7 13.3  nd 0  nd nd % 128 nd   40 nd nd nd nd nd nd nd nd nd 129 nd   30 nd nd nd nd nd nd nd nd nd 130 nd   29 nd nd <4000      nd nd nd nd nd nd 131 45   28  0 nd 46108     nd nd nd nd nd nd 132 nd   26 nd nd nd nd nd nd nd nd nd 133 nd   26 nd nd nd nd nd nd nd nd nd 134 nd   23 nd nd nd nd nd nd nd nd nd 135 nd   23 nd nd nd nd nd nd nd nd nd 136 >100000       21  0  67.9 0   5.2 0   0   0  nd nd 137 66975     21   5.2  68.7 0   0   5.5 3.5 5  nd nd 138 43856     19   12.2  77.1 4.6 17.1  12.6  14.4  0  nd nd 139 nd   18 nd nd nd nd nd nd nd nd nd 140 20195     18   10.8  79.6 0   20.6  13.3  10.4   4.2 nd nd 141 63.4 at 100   18  0  72.9 0   0   15.3  nd 44.5 56 nd μM % 142 nd   16 nd nd nd nd nd nd nd nd nd 143 28 at 100 μM %   15 12 91  0   12   0   8   18   nd nd 144 21175       7.5   7.5  80.6 0   3.6 0   6.2 0  nd nd 145 nd   14 nd nd nd nd nd nd nd nd nd 146  1 at 100 μM %   12  3 87  0   11   1   0   22   nd nd 147 nd   11 nd nd nd nd nd nd nd nd nd 148 52 at 100 μM %   11  9 91  7   32   8   12   30   nd nd 149 nd   11 nd nd nd nd nd nd nd nd nd 150 nd   10 nd nd nd nd nd nd nd nd nd 151 nd   10 nd nd nd nd nd nd nd nd nd 152 nd    9 nd nd nd nd nd nd nd nd nd 153 56 at 100 μM %     8.5  8 84  0   16   11   16   9  nd nd 154 27 at 100 μM %     8.3  0 4 0   7   0   1   15   nd nd 155 52 at 100 μM %     8.2 18 83  3   19   9   12   30   nd nd 156 46 at 100 μM %     7.5  0 5 0   17   0   7   15   nd nd 157 nd    7 nd nd nd nd nd nd nd nd nd 158 55 at 100 μM %     7.1  8 93  0   2   1   10   13   nd nd 159 nd    7 nd nd nd nd nd nd nd nd nd 160 55 at 100 μM %    6  3 94  2   23   1   14   30   nd nd 161 nd    6 nd nd nd nd nd nd nd nd nd 162 nd     12.5 nd nd nd nd nd nd nd nd nd 163 nd   24 nd nd nd nd nd nd nd nd nd 164 nd   24 nd nd nd nd nd nd nd nd nd 165 nd   22 nd nd nd nd nd nd nd nd nd 166 nd   18 nd nd nd nd nd nd nd nd nd 167 35134     18 19  60.2 6.4 0   19.6  11.1   0.2 nd nd 168 11155     18   12.8  72.9 1.2 0   5.6 5.7  4.6 nd nd 169 20295     18   10.8  79.6 0   20.6 13.3  10.4   4.2 nd nd 170 nd   16 nd nd nd nd nd nd nd nd nd 171 nd   13 nd nd nd nd nd nd nd nd nd 172 nd   13 nd nd nd nd nd nd nd nd nd 173 nd   12 nd nd nd nd nd nd nd nd nd 174 56 at 100   12  7 85  0   11   3   1   10   nd nd μM % 175 nd   12 nd nd nd nd nd nd nd nd nd 176 69 at 100     10.3  7 55  2   15   1   8   17   nd nd μM % 177 54 at 100    7  5 86  3   17   7   12   15   nd nd μM % 178 nd    6 nd nd nd nd nd nd nd nd nd 179 nd   50 >100000,  76.0 nd nd nd nd 0  nd nd IC50 (nmol) 180 120  nd 60 nd nd nd nd nd <100     nd nd 181 127  nd 113  nd nd nd nd nd 40   nd nd 182 111  nd 59 nd nd nd nd nd 39   nd nd 183 243  nd 146  nd nd nd nd nd 25   nd nd 184 221  nd 48 nd nd nd nd nd 27   nd nd 185 514  nd 126  nd nd nd nd nd 14   nd nd 186 337  nd 99 nd nd nd nd nd 15   nd nd 187 158  nd 39 nd nd nd nd nd <100     nd nd 188 105  nd 34 nd nd nd nd nd <100     nd nd 189 164  nd 39 nd nd nd nd nd <100     nd nd 190 1500  nd 172  nd nd nd nd nd <100     nd nd 191 400  nd 66 nd nd nd nd nd 21   nd nd 192 650  nd 72 nd nd nd nd nd 16   nd nd 193 431  nd 35 nd nd nd nd nd 6  nd nd 194 1570  nd 431  nd nd nd nd nd 9  nd nd 195 4000  nd 108  nd nd nd nd nd 12   nd nd 196 2165  nd 70 nd nd nd nd nd 52   nd nd Nd: not determined

The results of the experiment described in 2.5 above are indicated in Table 4 herein below.

TABLE 4 Ex. Stability human Plasma t_(1/2) (min) Stability rat Plasma t_(1/2) (min) 22 300 300 23 300 300 75 300 300 121 300 300 158 300 300

The results of the experiment described in 2.6 (PK), above, are indicated in Table 5 herein below.

TABLE 5 Administration route Intravenous Oral Dose (mg/kg) 5 50 Dose_(norm) (mg/kg) 5 5 AUC_(0-t) (ng · h/ml) 6044 782 AUC_(0-∞) (ng · h/ml) 6047 813 AUC_(0-∞ norm) (ng · h/ml) 6047 81 T_(max observed) (hours) 10752 464 T_(max norm) (hours) 10752 46 C_(max norm) (ng/ml) 0.08 0.25 β (hours⁻¹) Terminal t_(1/2) (hours) 0.5 0.87 Vd (ml/kg) 547 1008 % absorbed (F) 100% 1.3% (percentage of normalized AUC_(0-∞) po. against normalized AUC_(0-∞) i.v.)

The large inter-individual variation in plasma concentration of Ex. 75 was most pronounced after single oral administration (1 or i.v.: % C.V=6-68%, except for one value at the lowest measurable concentration 173%; for p.o. % C.V.: 113-173%).

Intravenous Administration

After intravenous administration of Ex. 75 at a dose level of 5 mg/kg body weight, Ex. 75 followed intravenous kinetic characteristics. After PK analysis, Ex 75 showed an extrapolated C_(initial) of 14069 ng/ml and a C_(max) observed of 10762 ng/ml at 5 min (0 083 hour). Plasma levels rapidly decreased to 5774 and 3455 ng/ml at 15 min and 30 min, respectively. From 1 to 2 hours plasma levels decreased with a terminal t_(1/2) of 0.46 hours to 18 ng/ml at 4 hours. The AUC_(0-t) and AUC₀-infinite amounted to 6044 and 6047 ng×h/ml, respectively; the initial distribution volume amounted to 355 ml/kg. The apparent distribution volume was 547 ml/kg.

Oral Administration

Alter oral administration of Ex 75 at a dose level of 50 mg/kg body weight, plasma levels of Ex. 75 followed oral kinetic characteristics. After PK analysis, Ex. 75 showed an observed C_(max) of 464 ng/ml at 0.25 hour (15 min). From 0.25 hours, plasma levels decreased with a terminal t_(1/2) of 0.87 hours to 24 ng/ml at 4 hours. The AUC_(0-t) and AUC_(0-infinite) amounted to 782 and 813 ng×h/ml. respectively. Taking into account the absorption of 1.3%, the apparent distribution volume was 1008 ml/kg.

Oral Versus Intravenous Administration

Due to the different dose levels between the oral group versus the i.v. group, values were compared after dose normalisation.

Compared to the normalized AUC_(0-infinite) value after i.v. administration of Ex. 75 (100%: 6047 ng-h/ml), the percentage of Ex. 75 absorbed (F) after oral administration amounted to 1.3% (81 ng×h/ml) at an about 234 times lower normalised C_(max) value after oral administration (46 versus 10762 ng/ml; Table 3). The apparent distribution volume after oral administration was about 1.8 fold higher than after i.v. administration (1008 versus 547 ml/kg).

REFERENCES

1. Barrtt, A. J. Methods in Enzymology 1981, 80, 561-565; Leatherbarrow, R. J. 1992, GraFit, Erithacus Software Ltd., Staines, U.K.

2. Mossman T. J. Immunol. Meth. 1983, 65:55-63

3. Berridge M V, Tan A S. Arch. Biochem. Biophys. 1993, 303:474-482 

The invention claimed is:
 1. A compound of the general formula (I)

wherein

is a dipeptide made up of two different amino acid building blocks, the dipeptide being ^(D)Pro-^(L)Pro(5RPhe), ^(D)Ala-^(L)Pro, ^(D)Ile-^(L)Pro, ^(D)Pro-^(L)Leu, ^(D)Pro-^(L)Glu, ^(D)Ala-^(L)Asp, ^(D)Asn-^(L)Pro, ^(D)Thr-^(L)Pro, ^(D)Asp-^(L)Pro, ^(D)Phe-^(L)Pro, ^(D)Arg-^(L)Pro, ^(D)Ser-^(L)Pro, ^(D)Val-^(L)Pro, ^(D)Pic-^(L)Pro, ^(D)Pro-^(L)Asp, ^(D)Pro-^(L)Phe, ^(D)Pro-^(L)Gln, ^(D)Pro-^(L)Ser, ^(D)Pro-^(L)Val, ^(D)Thr-^(L)Thr, ^(D)Lys-^(L)Glu, ^(D)Phe-^(L)Thr, ^(D)Pro-^(L)Ile, or ^(D)Gln-^(L)Gln, and Z is an undecapeptide chain made up of eleven amino acid residues, in which P1 is selected from Phe, Nle, OctG, or hPhe; P2 is Cys; P3 is Thr; P4 is selected from Lys or Ala; P5 is Ser; P6 is selected from Asp, Ile, OctG, or Cha; P7 is Pro; P8 is selected from Pro or Pro(4NHCOPhe); P9 is selected from Ile or Gln; P10 is Cys; and P11 is selected from Ser, Tyr, Gln, Cha, or 2Cl-Phe; two residues of Cys, which are present as the P2 and P10 residues, being linked by a disulfide bridge formed by replacement of the two —SH groups by one —S—S— group, in free form or in a pharmaceutically acceptable salt form.
 2. The compound according to claim 1, in which in the said undecapeptide chain P1 is Phe; P2 is Cys; P3 is Thr; P4 is Lys; P5 is Ser; P6 is Asp; P7 is Pro; P8 is Pro; P9 is Ile; P10 is Cys; and P11 is Ser.
 3. The compound according to claim 1, in which in the said undecapeptide chain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Ile; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Tyr.
 4. The compound according to claim 1, in which the template is ^(D)Pro-^(L)Pro(5RPhe), ^(D)Ala-^(L)Pro, ^(D)Ile-^(L)Pro, ^(D)Pro-^(L)Leu, ^(D)Pro-^(L)Glu, ^(D)Ala-^(L)Asp, ^(D)Asn-^(L)Pro, or ^(D)Thr-^(L)Pro, and in which in the said undecapeptide chain P1 is Phe; P2 is Cys; P3 is Thr; P4 is Lys; P5 is Ser; P6 is Asp; P7 is Pro; P8 is Pro; P9 is Ile; P10 is Cys; and P11 is Ser.
 5. The compound according to claim 1, in which the template is ^(D)Asp-^(L)Pro, ^(D)Phe-^(L)Pro, ^(D)Arg-^(L)Pro, ^(D)Ser-^(L)Pro, ^(D)val-^(L)Pro, ^(D)Pic-^(L)Pro, ^(D)Pro-^(L)Asp, ^(D)Pro-^(L)Phe, ^(D)Pro-^(L)Phe, ^(D)Pro-^(L)ser, ^(D)Pro-^(L)Val, ^(D)Thr-^(L)Thr, ^(D)Lys-^(L)Glu, ^(D)Phe-^(L)Thr, ^(D)Ala-^(L)Pro, or ^(D)Pro-^(L)Ile, and in which in the said undecapeptide chain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Ile; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Tyr.
 6. The compound according to claim 1, in which the template is ^(D)Lys-^(L)Glu, and in which in the said undecapeptide chain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is OctG; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Tyr.
 7. The compound according to claim 1, in which the template is ^(D)Pro-^(L)Gln, and in which in the said undecapeptide chain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Cha; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Gln.
 8. The compound according to claim 1, in which the template is ^(D)Lys-^(L)Glu, and in which in the said undecapeptide chain P1 is OctG; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Ile P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Tyr.
 9. The compound according to claim 1, in which the template is ^(D)Pro-^(L)Gln, and in which in the said undecapeptide chain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is OctG; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Tyr.
 10. The compound according to claim 1, in which the template is ^(D)Pro-^(L)Gln, and in which in the said undecapeptide chain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Cha; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Tyr.
 11. The compound according to claim 1, in which the template is ^(D)Gln-^(L)Gln, and in which in the said undecapeptide chain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Cha; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Cha.
 12. The compound according to claim 1, in which the template is ^(D)Pro-^(L)Gln, and in which in the said undecapeptide chain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Cha; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Cha.
 13. The compound according to claim 1, in which the template is ^(D)Pro-^(L)Gln, and in which in the said undecapeptide chain P1 is hPhe; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Ile; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Tyr.
 14. The compound according to claim 1, in which the template is ^(D)Lys-^(L)Glu, and in which in the said undecapeptide chain P1 is hPhe; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Ile; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Tyr.
 15. The compound according to claim 1, in which the template is ^(D)Pro-^(L)Gln, and in which in the said undecapeptide chain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Cha; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is 2Cl-Phe.
 16. The compound according to claim 1, in which the template is ^(D)Gln-^(L)Gln, and in which in the said undecapeptide chain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Cha; P7 is Pro; P8 is Pro(4NHCOPhe); P9 is Gln; P10 is Cys; and P11 is Gln.
 17. The compound according to claim 1, in which the template is ^(D)Pro-^(L)Gln, and in which in the said undecapeptide chain P1 is OctG; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Ile; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Tyr.
 18. The compound according to claim 1, in which the template is ^(D)Pro-^(L)Gln, and in which in the said undecapeptide chain P1 is OctG; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is OctG; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Gln.
 19. An enantiomer of the compound of formula I as defined in claim
 1. 20. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.
 21. The pharmaceutical composition according to claim 20 in a form suitable for oral, buccal, rectal, vaginal, topical, transdermal, transmucosal, pulmonary, injection, inhalation, or implantation administration.
 22. The pharmaceutical composition according to claim 20 in form of a tablet, a dragee, a capsule, a lozenge, a pill, a powder, a liquid, a solution, a syrup, an elixir, a slurry, a suspension, an emulsion, a gel, a cream, an ointment, a plaster, a spray, a nebulizer, an inhaler, an insufflator, a suppository, a sustained-release system, a long acting formulation, a depot preparation, or a liposome.
 23. A method for treating a disease by inhibiting a protease enzyme in a subject in need thereof, the method comprising administering an effective amount of the compound of claim 1 to said subject.
 24. The method according to claim 23, wherein said inhibition treats an infection in a healthy subject or slows the progression of an infection in an infected subject.
 25. The method according to claim 23, wherein the protease enzyme is Cathepsin G.
 26. The method according to claim 23, wherein the protease enzyme is elastase.
 27. The method according to claim 23, wherein the protease enzyme is tryptase.
 28. The method of claim 23, wherein the disease is selected from the group consisting of cancer, an inflammatory disease, an infection, a cardiovascular disease, an immunological disease, a neurodegenerative disease, and a pulmonary disease.
 29. A process for the manufacture of a compound according to claim 1 which process comprises (a) coupling an appropriately functionalized solid support with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position 5, 6 or 7, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (b) removing the N-protecting group from the product thus obtained; (c) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position nearer the N-terminal amino acid residue, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (d) removing the N-protecting group from the product thus obtained; (e) repeating steps (c) and (d) until the N-terminal amino acid residue has been introduced; (f) coupling the product thus obtained with a compound of the general formula

wherein

is as defined in claim 1 and X is an N-protecting group; (g) removing the N-protecting group from the product obtained in step (f); (h) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position 11, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (i) removing the N-protecting group from the product thus obtained; (j) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position farther away from position 11, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (k) removing the N-protecting group from the product thus obtained; (l) repeating steps (j) and (k) until all amino acid residues have been introduced; (m) optionally, selectively deprotecting one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated; (n) optionally, forming an interstrand linkage between side-chains of appropriate amino acid residues at positions 2 and 10; (o) detaching the product thus obtained from the solid support; (p) cyclizing the product cleaved from the solid support; (q) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, optionally, any protecting group(s) which may in addition be present in the molecule; and (r) optionally, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula I or into a different, pharmaceutically acceptable, salt.
 30. A modification of the process according to claim 29 for the manufacture of an enantiomer of the compound of formula (I), in which enantiomers of all chiral starting materials are used.
 31. A process for the manufacture of a compound according to claim 1 which process comprises (a′) coupling an appropriately functionalized solid support with a compound of the general formula

wherein

is as defined in claim 1 and X is an N-protecting group; (b′) removing the N-protecting group from the product obtained in step (a′); (c′) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position 11, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (d′) removing the N-protecting group from the product thus obtained; (e′) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position farther away from position, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (f′) removing the N-protecting group from the product thus obtained; (g′) repeating steps (e′) and (f′) until all amino acid residues have been introduced; (h′) optionally, selectively deprotecting one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated; (i′) optionally, forming an interstrand linkage between side-chains of appropriate amino acid residues at positions 2 and 10; (j′) detaching the product thus obtained from the solid support; (k′) cyclizing the product cleaved from the solid support; (l′) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, optionally, any protecting group(s) which may in addition be present in the molecule; and (m′) optionally, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula I or into a different, pharmaceutically acceptable, salt.
 32. A modification of the process according to claim 31 for the manufacture of an enantiomer of the compound of formula (I), in which enantiomers of all chiral starting materials are used. 